C. Fletcher, J. Bridge, P. Hogendoorn, F. Mertens, and . Eds, World Health Organization classification of tumours. Pathology and genetics of tumours of soft Tissue and bone, 2013.

M. A. Clark, C. Fisher, J. I. Thomas, and J. M. , Soft-tissue sarcomas in adults, N Engl J Med, vol.353, pp.701-712, 2005.

P. J. Woll, P. Reichardt, L. Cesne, A. Bonvalot, S. Azzarelli et al., Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial, Lancet Oncol, vol.13, issue.12, pp.70346-70353, 2012.
DOI : 10.1016/s1470-2045(12)70346-7

R. A. Gladdy, L. Qin, N. Moraco, N. P. Agaram, M. F. Brennan et al., Predictors of Survival and Recurrence in Primary Leiomyosarcoma, Ann Surg Oncol, vol.20, pp.1851-1858, 2013.

N. P. Agaram, L. Zhang, F. Leloarer, T. Silk, Y. Sung et al., Targeted exome sequencing profiles genetic alterations in leiomyosarcoma, Genes Chromosomes Cancer, vol.55, 2016.
DOI : 10.1002/gcc.22318
URL : http://europepmc.org/articles/pmc4715662?pdf=render

J. Yang, X. Du, K. Chen, A. Ylipää, A. Lazar et al., Genetic aberrations in soft tissue leiomyosarcoma, Cancer Lett, vol.275, pp.1-8, 2009.
DOI : 10.1016/j.canlet.2008.06.013
URL : http://europepmc.org/articles/pmc2674272?pdf=render

L. Gibault, C. Ferreira, G. Pérot, A. Audebourg, F. Chibon et al., From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway in leiomyosarcomas

C. Fletcher, J. Bridge, P. Hogendoorn, and F. Mertens, World Health Organization classification of tumours. Pathology and genetics of tumours of soft Tissue and bone, 2013.

M. A. Clark, C. Fisher, I. Judson, and J. M. Thomas, Soft-tissue sarcomas in adults, N. Engl. J. Med, vol.353, pp.701-711, 2005.

P. J. Woll, P. Reichardt, A. Le-cesne, S. Bonvalot, A. Azzarelli et al.,

P. Bramwell and . Hohenberger, EORTC Soft Tissue and Bone Sarcoma Group and the NCIC Clinical Trials Group Sarcoma Disease Site Committee, Adjuvant chemotherapy with doxorubicin, ifosfamide, and lenograstim for resected soft-tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial, Lancet Oncol, vol.13, pp.1045-1054, 2012.

R. A. Gladdy, L. Qin, N. Moraco, N. P. Agaram, M. F. Brennan et al., Predictors of Survival and Recurrence in Primary Leiomyosarcoma, Ann. Surg. Oncol, vol.20, pp.1851-1857, 2013.

N. P. Agaram, L. Zhang, F. Leloarer, T. Silk, Y. Sung et al., Targeted exome sequencing profiles genetic alterations in leiomyosarcoma, Genes. Chromosomes Cancer, vol.55, pp.124-130, 2016.

L. Guillou and A. Aurias, Soft tissue sarcomas with complex genomic profiles, Virchows Arch, Int. J. Pathol, vol.456, pp.201-217, 2010.

A. Italiano, P. Lagarde, C. Brulard, P. Terrier, M. Laë et al.,

J. Michels, M. Trassard, A. Cioffi, S. Piperno-neumann, C. Chevreau et al.,

N. Delcambre, N. Isambert, J. Penel, S. Bay, A. Bonvalot et al.,

. Chibon, Genetic profiling identifies two classes of soft-tissue leiomyosarcomas with distinct clinical characteristics, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.19, pp.1190-1196, 2013.

J. Hu, U. N. Rao, S. Jasani, V. Khanna, K. Yaw et al., Loss of DNA copy number of 10q is associated with aggressive behavior of leiomyosarcomas: a comparative genomic hybridization study, Cancer Genet. Cytogenet, vol.161, pp.20-27, 2005.

L. Gibault, C. Ferreira, G. Pérot, A. Audebourg, F. Chibon et al.,

P. Vacher-lavenu, J. Terrier, A. Coindre, and . Aurias, From PTEN loss of expression to RICTOR role in smooth muscle differentiation: complex involvement of the mTOR pathway RESULTATS EXPERIMENTAUX Partie 2-Résistance secondaire au ciblage de la voie PI3K/mTOR

, Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc, vol.25, pp.197-211, 2012.

E. Hernando, E. Charytonowicz, M. E. Dudas, S. Menendez, I. Matushansky et al.,

D. Socci, N. Behrendt, L. Ma, R. G. Maki, P. P. Pandolfi et al., The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas, Nat. Med, vol.13, pp.748-753, 2007.

C. Forscher, M. Mita, and R. Figlin, Targeted therapy for sarcomas, Biol. Targets Ther, vol.8, pp.91-105, 2014.

A. Italiano, M. Kind, E. Stoeckle, N. Jones, J. Coindre et al., Temsirolimus in advanced leiomyosarcomas: patterns of response and correlation with the activation of the mammalian target of rapamycin pathway, Anticancer. Drugs, vol.22, pp.463-467, 2011.

A. Carracedo, L. Ma, J. Teruya-feldstein, F. Rojo, L. Salmena et al.,

G. Sasaki, S. C. Thomas, A. Kozma, C. Papa, L. C. Nardella et al., Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer, J. Clin. Invest, vol.118, pp.3065-3074, 2008.

K. E. O'reilly, F. Rojo, Q. She, D. Solit, G. B. Mills et al., mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt, vol.66, pp.1500-1508, 2006.

A. Carracedo and P. P. Pandolfi, The PTEN-PI3K pathway: of feedbacks and cross-talks, Oncogene, vol.27, pp.5527-5541, 2008.

G. D. Demetri, S. P. Chawla, I. Ray-coquard, A. Le-cesne, A. P. Staddon et al.,

J. Dodion and . Blay, Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.31, pp.2485-2492, 2013.

J. A. Engelman, J. Luo, and L. C. Cantley, The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism, Nat. Rev. Genet, vol.7, pp.606-619, 2006.

L. Julien, A. Carriere, J. Moreau, and P. P. Roux, mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling, vol.30, pp.908-921, 2010.

M. Nishimoto, S. Miyagi, T. Yamagishi, T. Sakaguchi, H. Niwa et al., Oct-3/4 Maintains the Proliferative Embryonic Stem Cell State via Specific Binding to a

, Variant Octamer Sequence in the Regulatory Region of the UTF1 Locus, Mol. Cell. Biol, vol.25, pp.5084-5094, 2005.

J. Nichols, B. Zevnik, K. Anastassiadis, H. Niwa, and D. Klewe-nebenius,

A. Schöler and . Smith, Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4, Cell, vol.95, pp.379-391, 1998.

D. O'carroll, S. Erhardt, M. Pagani, S. C. Barton, M. A. Surani et al., The polycomb-group gene Ezh2 is required for early mouse development, Mol. Cell. Biol, vol.21, pp.4330-4336, 2001.

H. A. Burris, Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway, Cancer Chemother. Pharmacol, vol.71, pp.829-842, 2013.

Y. Ma and S. Zhao, Prognostic values of aldehyde dehydrogenase 1 isoenzymes in ovarian cancer, OncoTargets Ther, vol.9, pp.1981-1988, 2016.

K. Li, X. Guo, Z. Wang, X. Li, Y. Bu et al., The prognostic roles of ALDH1 isoenzymes in gastric cancer, OncoTargets Ther, vol.9, pp.3405-3414, 2016.

M. Flahaut, N. Jauquier, N. Chevalier, K. Nardou, K. Balmas-bourloud et al.,

C. Barras, N. Widmann, R. Gross, A. Renella, and . Mühlethaler-mottet, Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma, BMC Cancer, vol.16, p.781, 2016.

S. Wu, W. Xue, X. Huang, X. Yu, M. Luo et al., Distinct prognostic values of ALDH1 isoenzymes in breast cancer, Tumour Biol. J. Int. Soc

, Oncodevelopmental Biol. Med, vol.36, pp.2421-2426, 2015.

N. M. Jones, M. R. Rowe, P. R. Shepherd, and M. J. Mcconnell, Targeted inhibition of dominant PI3-kinase catalytic isoforms increase expression of stem cell genes in glioblastoma cancer stem cell models, Int. J. Oncol, vol.49, pp.207-216, 2016.

N. E. Bhola, V. M. Jansen, J. P. Koch, H. Li, L. Formisano et al., Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population, Cancer Res, vol.76, pp.440-452, 2016.

L. A. Boyer, K. Plath, J. Zeitlinger, T. Brambrink, L. A. Medeiros et al.,

M. Wernig, A. Tajonar, M. K. Ray, G. W. Bell, A. P. Otte et al.,

R. Young and . Jaenisch, Polycomb complexes repress developmental regulators in murine embryonic stem cells, Nature, vol.441, pp.349-353, 2006.

X. Shen, Y. Liu, Y. Hsu, Y. Fujiwara, J. Kim et al., EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency, Mol. Cell, vol.32, pp.491-502, 2008.

H. Richly, L. Aloia, and L. Di-croce, Roles of the Polycomb group proteins in stem cells and cancer, Cell Death Dis, vol.2, p.204, 2011.

L. E. Moritz and R. C. Trievel, Structure, mechanism, and regulation of polycomb repressive complex 2, J. Biol. Chem, 2017.

C. Kadoch and G. R. Crabtree, Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics, Sci. Adv, vol.1, p.1500447, 2015.

B. T. Wilhelm and J. Landry, RNA-Seq-quantitative measurement of expression through massively parallel RNA-sequencing, Methods San Diego Calif, vol.48, pp.249-257, 2009.

, najoshi, sickle: Windowed Adaptive Trimming for fastq files using quality, 2017.

J. S. John, SeqPrep: Tool for stripping adaptors and/or merging paired reads with overlap into single reads, 2017.

B. Langmead and S. L. Salzberg, Fast gapped-read alignment with Bowtie 2, Nat. Methods, vol.9, pp.357-359, 2012.

H. Li, B. Handsaker, A. Wysoker, T. Fennell, J. Ruan et al., Genome Project Data Processing Subgroup, The Sequence Alignment/Map format and SAMtools, Bioinforma. Oxf. Engl, vol.25, pp.2078-2079, 1000.

S. Anders, P. T. Pyl, and W. Huber, HTSeq-a Python framework to work with high-throughput sequencing data, Bioinforma. Oxf. Engl, vol.31, pp.166-169, 2015.

C. W. Law, Y. Chen, W. Shi, and G. K. Smyth, voom: Precision weights unlock linear model analysis tools for RNA-seq read counts, Genome Biol, vol.15, p.29, 2014.

M. E. Ritchie, B. Phipson, D. Wu, Y. Hu, C. W. Law et al., limma powers differential expression analyses for RNA-sequencing and microarray studies, Nucleic Acids Res, vol.43, p.47, 2015.

Y. Benjamini and Y. Hochberg, Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing, J. R. Stat. Soc. Ser. B Methodol, vol.57, pp.289-300, 1995.

A. Subramanian, P. Tamayo, V. K. Mootha, S. Mukherjee, B. L. Ebert et al., Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles, Proc. Natl. Acad. Sci. U. S. A, vol.102, pp.15545-15550, 2005.

C. Fletcher, K. K. Unni, and F. Mertens, Pathology and genetics of tumours of soft tissue and bone, MDM2 antagonists synergize with PI3K/mTOR inhibition in welldifferentiated/dedifferentiated liposarcomas REFERENCES 1, 2002.

C. Mussi, P. Collini, and R. Miceli, The prognostic impact of dedifferentiation in retroperitoneal liposarcoma: a series of surgically treated patients at a single institution, Cancer, vol.113, pp.1657-1665, 2008.

J. M. Coindre, F. Pedeutour, and A. Aurias, Well-differentiated and dedifferentiated liposarcomas, Virchows Arch, vol.456, pp.167-179, 2010.
URL : https://hal.archives-ouvertes.fr/hal-00437654

D. R. Lucas, A. G. Nascimento, B. K. Sanjay, and M. G. Rock, Welldifferentiated liposarcoma. The Mayo Clinic experience with 58 cases, Am J Clin Pathol, vol.102, pp.677-683, 1994.

W. H. Henricks, Y. C. Chu, J. R. Goldblum, and S. W. Weiss, Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation, Am J Surg Pathol, vol.21, pp.271-281, 1997.

K. M. Dalal, M. W. Kattan, and C. R. Antonescu, Subtype specific prognostic nomogram for patients with primary liposarcoma of the retroperitoneum, extremity, or trunk

, Ann Surg, vol.244, pp.381-391, 2006.

S. Singer, C. R. Antonescu, E. Riedel, and M. F. Brennan, Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma

, Ann Surg, vol.238, pp.370-351, 2003.

A. Italiano, M. Toulmonde, A. Cioffi, N. Penel, N. Isambert et al., Advanced well-differentiated/ dedifferentiated liposarcomas: role of chemotherapy and survival, Ann Oncol, vol.23, pp.1601-1608, 2012.

A. Italiano, L. Bianchini, and F. Keslair, HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon, Int J Cancer, vol.122, pp.2233-2274, 2008.
URL : https://hal.archives-ouvertes.fr/hal-00320104

L. T. Vassilev, B. T. Vu, B. Graves, D. Carvajal, F. Podlaski et al., In vivo activation of the TP53 pathway by small-molecule antagonists of MDM2, Science, vol.303, p.844, 2004.

R. Blay, J. Y. Italiano, A. , L. Cesne, A. Penel et al., Effect of the MDM2 antagonist RG7112 on the TP53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-ofmechanism study, Lancet Oncol, vol.13, issue.11, pp.1133-1173, 2012.

L. L. Siu, A. Italiano, W. H. Miller, J. Y. Blay, J. A. Gietema et al., Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent secondgeneration MDM2 antagonist, in patients (pts) with solid tumors, J Clin Oncol, vol.32, 2014.

A. Gutierrez, E. L. Snyder, A. Marino-enriquez, Y. X. Zhang, S. Sioletic et al., Aberrant AKT activation drives well-differentiated liposarcoma, Proc Natl Acad Sci U S A, vol.108, pp.16386-16395, 2011.

K. B. Smith, L. M. Tran, B. M. Tam, E. M. Shurell, Y. Li et al., Novel dedifferentiated liposarcoma xenograft models reveal PTEN down-regulation as a malignant signature and response to PI3K pathway inhibition, Am J Pathol, vol.182, pp.1400-1411, 2013.

L. D. Mayo, A phosphatidylinositol 3-kinaseyAkt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus, Proc Natl Acad Sci U S A, vol.98, pp.11598-11603, 2001.

V. Stambolic, Regulation of PTEN Transcription by TP53, Mol Cell, vol.8, pp.317-325, 2001.

L. C. Trotman, PTEN and TP53: Who will get the upper hand?, Cancer Cell, vol.3, pp.97-99, 2003.

Y. Tang, TP53 Down-Regulates Phosphatase and Tensin Homologue Deleted on Chromosome 10 Protein Stability Partially through Caspase-Mediated Degradation in Cells with Proteasome Dysfunction, Cancer Res, vol.66, pp.6139-6148, 2006.

Y. Tang, PTEN Autoregulates Its Expression by Stabilization of TP53 in a Phosphatase-Independent Manner, Cancer Res, vol.66, pp.736-742, 2006.

C. R. Müller, Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin3A, Int J Cancer, vol.121, 2007.

K. I. Pishas, Nutlin3a is a potential therapeutic for ewing sarcoma, Clin Cancer Res, vol.17, p.494504, 2011.

B. Wang, MDM2 inhibitor Nutlin3a suppresses proliferation and promotes apoptosis in osteosarcoma cells, Acta Biochim Biophys Sin (Shanghai), vol.44, pp.685-91, 2012.

L. Coll-mulet, D. Iglesias-serret, and A. F. Santidrian, MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells, Blood, vol.107, pp.4109-4123, 2006.

K. Kojima, M. Konopleva, and T. Mcqueen, Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcriptiondependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia, Blood, vol.108, pp.993-1000, 2006.
DOI : 10.1182/blood-2005-12-5148
URL : http://www.bloodjournal.org/content/108/3/993.full.pdf

H. Ohnstad, E. B. Paulsen, P. Noordhuis, M. Berg, R. A. Lothe et al., MDM2 antagonist Nutlin3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines, BMC Cancer, vol.11, pp.1-11, 2011.

S. P. Chawla, J. Y. Blay, A. Italiano, M. Gutierrez, L. Cesne et al., Phase Ib study of RG7112 with doxorubicin (D) in advanced soft tissue sarcoma (ASTS), J Clin Oncol, vol.31, 2013.

A. G. Abraham and E. O'neill, PI3K/Akt-mediated regulation of TP53 in cancer, Biochem Soc Trans, vol.42, pp.798-803, 2014.

L. D. Mayo and D. B. Donner, The PTEN, Mdm2, TP53 tumor suppressor-oncoprotein network, Trends Biochem Sci, vol.27, pp.462-469, 2002.
DOI : 10.1016/s0968-0004(02)02166-7

A. Y. Saiki, S. Caenepeel, D. Yu, J. A. Lofgren, T. Osgood et al., , p.2

, antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways, Oncotarget, vol.5, pp.2030-2073, 2014.

N. Akeno, A. L. Miller, X. Ma, and K. A. Wikenheiser-brokamp, p53 suppresses carcinoma progression by inhibiting mTOR pathway activation, Oncogene, vol.34, pp.589-99, 201529.

A. Herzog, Y. Bian, V. Broek, R. Hall, B. Coupar et al., Van Waes C. PI3K/mTOR inhibitor PF04691502 antitumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer, Clin Cancer Res, vol.19, pp.3808-3827, 2013.

T. C. Chou and P. Talalay, Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors, Adv Enzyme Regul, vol.22, pp.3808-3827, 1984.

F. Abbasi, R. Mahmudlu, Y. Nikniaz, R. , and M. , Primary Cutaneous Leiomyosarcoma in a Young Patient Previously Misdiagnosed as Pleomorphic Fibroma, Iran. J. Pathol, vol.10, pp.69-73, 2015.

N. P. Agaram, L. Zhang, F. Leloarer, T. Silk, Y. Sung et al., Targeted exome sequencing profiles genetic alterations in leiomyosarcoma, Genes. Chromosomes Cancer, vol.55, pp.124-130, 2016.

D. R. Alessi, M. Andjelkovic, B. Caudwell, P. Cron, N. Morrice et al., Mechanism of activation of protein kinase B by insulin and IGF-1, EMBO J, vol.15, pp.6541-6551, 1996.

A. M. Al-khouri, Y. Ma, S. H. Togo, S. Williams, and T. Mustelin, Cooperative phosphorylation of the tumor suppressor phosphatase and tensin homologue (PTEN) by casein kinases and glycogen synthase kinase 3beta, J. Biol. Chem, vol.280, pp.35195-35202, 2005.

, AJCC Cancer Staging Manual, American Joint Comittee on Cancer, 2017.

M. Andjelkovi?, T. Jakubowicz, P. Cron, X. F. Ming, J. W. Han et al., Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors, Proc. Natl. Acad. Sci. U. S. A, vol.93, pp.5699-5704, 1996.

M. Andjelkovi?, D. R. Alessi, R. Meier, A. Fernandez, N. J. Lamb et al., Role of translocation in the activation and function of protein kinase B, J. Biol. Chem, vol.272, pp.31515-31524, 1997.

K. Antman, J. Crowley, S. P. Balcerzak, S. E. Rivkin, G. R. Weiss et al., An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.11, pp.1276-1285, 1993.

A. Aurias, C. Rimbaut, D. Buffe, J. Dubousset, M. et al., Chromosomal translocations in Ewing's sarcoma, N. Engl. J. Med, vol.309, pp.496-498, 1983.

O. Awad, J. T. Yustein, P. Shah, N. Gul, V. Katuri et al., High ALDH activity identifies chemotherapy-resistant Ewing's sarcoma stem cells that retain sensitivity to EWS-FLI1 inhibition, PloS One, vol.5, 2010.

Y. Babichev, L. Kabaroff, A. Datti, D. Uehling, M. Isaac et al., PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma, J. Transl. Med, vol.14, p.67, 2016.

J. M. Backer, The regulation and function of Class III PI3Ks: novel roles for Vps34, Biochem. J, vol.410, pp.1-17, 2008.

M. Balic, H. Lin, L. Young, D. Hawes, A. Giuliano et al., Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.12, pp.5615-5621, 2006.

M. L. Ballinger, D. L. Goode, I. Ray-coquard, P. A. James, G. Mitchell et al., Monogenic and polygenic determinants of sarcoma risk: an international genetic study, Lancet Oncol, vol.17, pp.1261-1271, 2016.

S. Bao, Q. Wu, R. E. Mclendon, Y. Hao, Q. Shi et al., Glioma stem cells promote radioresistance by preferential activation of the DNA damage response, Nature, vol.444, pp.756-760, 2006.

J. Barretina, B. S. Taylor, S. Banerji, A. H. Ramos, M. Lagos-quintana et al., Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy, Nat. Genet, vol.42, pp.715-721, 2010.

T. M. Bauer, M. R. Patel, and J. R. Infante, Targeting PI3 kinase in cancer, Pharmacol. Ther, vol.146, pp.53-60, 2015.

C. M. Becker, R. K. Oberoi, S. J. Mcfarren, D. M. Muldoon, D. H. Pafundi et al., Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma, Neuro-Oncol, vol.17, pp.1210-1219, 2015.

I. Ben-sahra and B. D. Manning, mTORC1 signaling and the metabolic control of cell growth, Curr. Opin. Cell Biol, vol.45, pp.72-82, 2017.

P. T. Bhaskar and N. Hay, The two TORCs and Akt, Dev. Cell, vol.12, pp.487-502, 2007.

J. A. Biegel, J. Y. Zhou, L. B. Rorke, C. Stenstrom, L. M. Wainwright et al., Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors, Cancer Res, vol.59, pp.74-79, 1999.

T. Boam, A. Hueschelrath, L. Tho, T. M. Costa, . Da et al., , 2016.

, Managing Soft Tissue Sarcomas in a Developing Health System, World J. Surg, vol.40, pp.1542-1549

L. Bozulic, B. Surucu, D. Hynx, and B. A. Hemmings, PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival, Mol. Cell, vol.30, pp.203-213, 2008.

A. Bradshaw, A. Wickremesekera, H. D. Brasch, A. M. Chibnall, P. F. Davis et al., Cancer Stem Cells in Glioblastoma Multiforme. Front. Surg, vol.3, p.48, 2016.

C. Brock, M. Schaefer, H. P. Reusch, C. Czupalla, M. Michalke et al., Roles of G beta gamma in membrane recruitment and activation of p110 gamma/p101 phosphoinositide 3-kinase gamma, J. Cell Biol, vol.160, pp.89-99, 2003.

J. S. Brown and U. Banerji, Maximising the potential of AKT inhibitors as anticancer treatments, Pharmacol. Ther, vol.172, pp.101-115, 2017.

T. M. Cardillo, P. Trisal, R. Arrojo, D. M. Goldenberg, C. et al., Targeting both IGF-1R and mTOR synergistically inhibits growth of renal cell carcinoma in vitro, BMC Cancer, vol.13, p.170, 2013.

A. Carracedo, L. Ma, J. Teruya-feldstein, F. Rojo, L. Salmena et al., Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer, J. Clin. Invest, vol.118, pp.3065-3074, 2008.

A. Carriere, Y. Romeo, H. A. Acosta-jaquez, J. Moreau, E. Bonneil et al., ERK1/2 phosphorylate Raptor to promote Ras-dependent activation of mTOR complex 1 (mTORC1), J. Biol. Chem, vol.286, pp.567-577, 2011.

C. Chan, U. Jo, A. Kohrman, A. H. Rezaeian, P. Chou et al., Posttranslational regulation of Akt in human cancer, Cell Biosci, vol.4, p.59, 2014.

T. O. Chan, S. E. Rittenhouse, and P. N. Tsichlis, AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation, Annu. Rev. Biochem, vol.68, pp.965-1014, 1999.

L. Chang, P. H. Graham, J. Hao, J. Ni, J. Bucci et al., Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance, Cell Death Dis, vol.4, p.875, 2013.

Y. Chang, E. Cesarman, M. S. Pessin, F. Lee, J. Culpepper et al., Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma, Science, vol.266, pp.1865-1869, 1994.

M. Chen, C. P. Pratt, M. E. Zeeman, N. Schultz, B. S. Taylor et al., Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression, Cancer Cell, vol.20, pp.173-186, 2011.

H. Cheng, Y. Zou, J. S. Ross, K. Wang, X. Liu et al., RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors, Cancer Discov, vol.5, pp.1262-1270, 2015.

A. Cheraghchi-bashi, C. A. Parker, E. Curry, J. Salazar, H. Gungor et al., A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway, Oncotarget, vol.6, pp.41736-41749, 2015.

S. Clément, U. Krause, F. Desmedt, J. F. Tanti, J. Behrends et al., The lipid phosphatase SHIP2 controls insulin sensitivity, Nature, vol.409, pp.92-97, 2001.

D. Coggon, G. Ntani, E. C. Harris, N. Jayakody, P. et al., Soft tissue sarcoma, non-Hodgkin's lymphoma and chronic lymphocytic leukaemia in workers exposed to phenoxy herbicides: extended follow-up of a UK cohort, Occup. Environ. Med, vol.72, pp.435-441, 2015.

J. M. Coindre, M. Trojani, G. Contesso, M. David, J. Rouesse et al., Reproducibility of a histopathologic grading system for adult soft tissue sarcoma, Cancer, vol.58, pp.306-309, 1986.

J. M. Coindre, P. Terrier, N. B. Bui, F. Bonichon, F. Collin et al., Prognostic factors in adult patients with locally controlled soft tissue sarcoma. A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.14, pp.869-877, 1996.

K. D. Courtney, R. B. Corcoran, and J. A. Engelman, The PI3K Pathway As Drug Target in Human Cancer, J. Clin. Oncol, vol.28, pp.1075-1083, 2010.

T. Cuppens, D. Annibali, A. Coosemans, J. Trovik, N. Ter-haar et al., Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.23, pp.1274-1285, 2017.

G. D. Demetri, M. Von-mehren, R. L. Jones, M. L. Hensley, S. M. Schuetze et al., Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.34, pp.786-793, 2016.

N. Dennis, M. Francis, L. , and G. , Soft tissue sarcoma, incidence and survival; report on tumours diagnosed between, 1985.

B. R. Dey, K. Frick, W. Lopaczynski, S. P. Nissley, and R. W. Furlanetto, Evidence for the direct interaction of the insulin-like growth factor I receptor with IRS-1, Shc, and Grb10, Mol. Endocrinol. Baltim. Md, vol.10, pp.631-641, 1996.

J. E. Dick, Stem cell concepts renew cancer research, Blood, vol.112, pp.4793-4807, 2008.

R. Dienstmann, J. Rodon, V. Serra, and J. Tabernero, Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors, Mol. Cancer Ther, vol.13, pp.1021-1031, 2014.

Q. Ding, X. He, J. Hsu, W. Xia, C. Chen et al., Degradation of Mcl-1 by beta-TrCP mediates glycogen synthase kinase 3-induced tumor suppression and chemosensitization, Mol. Cell. Biol, vol.27, pp.4006-4017, 2007.

S. O. Dolly, A. J. Wagner, J. C. Bendell, H. L. Kindler, L. M. Krug et al., Phase I Study of Apitolisib (GDC0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.22, pp.2874-2884, 2016.

V. S. Donnenberg and A. D. Donnenberg, Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis, J. Clin. Pharmacol, vol.45, pp.872-877, 2005.
DOI : 10.1177/0091270005276905

F. Ducimetière, A. Lurkin, D. Ranchère-vince, A. Decouvelaere, M. Péoc'h et al., Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing, PloS One, vol.6, 2011.

F. J. Dumont, M. J. Staruch, T. Grammer, J. Blenis, C. A. Kastner et al., Dominant mutations confer resistance to the immunosuppressant, rapamycin, in variants of a T cell lymphoma, Cell. Immunol, vol.163, pp.70-79, 1995.

K. Düvel, J. L. Yecies, S. Menon, P. Raman, A. I. Lipovsky et al., Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol. Cell, vol.39, pp.171-183, 2010.

M. Ebner, I. Lu?i?, T. A. Leonard, Y. , and I. , PI(3,4,5)P3 Engagement Restricts Akt Activity to Cellular Membranes, Mol. Cell, vol.65, pp.416-431, 2017.
DOI : 10.1016/j.molcel.2016.12.028

M. Elkabets, S. Vora, D. Juric, N. Morse, M. Mino-kenudson et al., mTORC1 inhibition is required for sensitivity to PI3K p110? inhibitors in PIK3CA-mutant breast cancer, Sci. Transl. Med, vol.5, 2013.
DOI : 10.1126/scitranslmed.3005747
URL : http://europepmc.org/articles/pmc3935768?pdf=render

O. Elmokh, D. Ruffieux-daidié, M. A. Roelli, A. Stooss, W. A. Phillips et al., Combined MEK and Pi3'-kinase inhibition reveals synergy in targeting thyroid cancer in vitro and in vivo, Oncotarget, vol.8, pp.24604-24620, 2017.

W. El-rifai, M. Sarlomo-rikala, S. Knuutila, and M. Miettinen, DNA copy number changes in development and progression in leiomyosarcomas of soft tissues, Am. J. Pathol, vol.153, pp.985-990, 1998.

M. Escrivà, S. Peiró, N. Herranz, P. Villagrasa, N. Dave et al., Repression of PTEN phosphatase by Snail1 transcriptional factor during gamma radiation-induced apoptosis, Mol. Cell. Biol, vol.28, pp.1528-1540, 2008.

V. Facchinetti, W. Ouyang, H. Wei, N. Soto, A. Lazorchak et al., The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C, EMBO J, vol.27, pp.1932-1943, 2008.

M. Falasca and T. Maffucci, Regulation and cellular functions of class II phosphoinositide 3-kinases, Biochem. J, vol.443, pp.587-601, 2012.
DOI : 10.1042/bj20120008
URL : http://www.biochemj.org/content/ppbiochemj/443/3/587.full.pdf

G. Farshid, M. Pradhan, J. Goldblum, and S. W. Weiss, Leiomyosarcoma of somatic soft tissues: a tumor of vascular origin with multivariate analysis of outcome in 42 cases, Am. J. Surg. Pathol, vol.26, pp.14-24, 2002.

C. G. Fedele, L. M. Ooms, M. Ho, J. Vieusseux, S. A. O'toole et al., Inositol polyphosphate 4phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers, Proc. Natl. Acad. Sci. U. S. A, vol.107, pp.22231-22236, 2010.
DOI : 10.1073/pnas.1015245107
URL : http://www.pnas.org/content/107/51/22231.full.pdf

A. Ferrari, U. Dirksen, and S. Bielack, Sarcomas of Soft Tissue and Bone, Prog. Tumor Res, vol.43, pp.128-141, 2016.

J. P. Fields and E. B. Helwig, Leiomyosarcoma of the skin and subcutaneous tissue, Cancer, vol.47, pp.156-169, 1981.

C. D. Fletcher, The evolving classification of soft tissue tumours-an update based on the new 2013 WHO classification, Histopathology, vol.64, pp.2-11, 2014.

C. Fletcher, J. Bridge, P. Hogendoorn, and M. , World Health Organization classification of tumours. Pathology and genetics of tumours of soft Tissue and bone, 2013.

T. M. Foley, S. N. Payne, C. A. Pasch, A. E. Yueh, D. R. Van-de-hey et al., Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations, Mol. Cancer Res. MCR, vol.15, pp.317-327, 2017.
DOI : 10.1158/1541-7786.mcr-16-0256-t

J. H. Francis, R. A. Kleinerman, J. M. Seddon, A. , and D. H. , Increased risk of secondary uterine leiomyosarcoma in hereditary retinoblastoma, Gynecol. Oncol, vol.124, pp.254-259, 2012.
DOI : 10.1016/j.ygyno.2011.10.019
URL : http://europepmc.org/articles/pmc3264733?pdf=render

M. Frech, M. Andjelkovic, E. Ingley, K. K. Reddy, J. R. Falck et al., High affinity binding of inositol phosphates and phosphoinositides to the pleckstrin homology domain of RAC/protein kinase B and their influence on kinase activity, J. Biol. Chem, vol.272, pp.8474-8481, 1997.

R. E. Friedrich, M. Hartmann, and V. F. Mautner, Malignant peripheral nerve sheath tumors (MPNST) in NF1-affected children, Anticancer Res, vol.27, pp.1957-1960, 2007.

R. Fritsche-guenther, F. Witzel, A. Sieber, R. Herr, N. Schmidt et al., Strong negative feedback from Erk to Raf confers robustness to MAPK signalling, Mol. Syst. Biol, vol.7, p.489, 2011.
DOI : 10.1038/msb.2011.27
URL : http://msb.embopress.org/content/7/1/489.full.pdf

S. Galper, R. Gelman, A. Recht, B. Silver, A. Kohli et al., Second nonbreast malignancies after conservative surgery and radiation therapy for early-stage breast cancer, Int. J. Radiat. Oncol. Biol. Phys, vol.52, pp.406-414, 2002.
DOI : 10.1016/s0360-3016(01)02661-x

X. Gan, J. Wang, C. Wang, E. Sommer, T. Kozasa et al., PRR5L degradation promotes mTORC2mediated PKC-? phosphorylation and cell migration downstream of G?12, Nat. Cell Biol, vol.14, pp.686-696, 2012.

T. Gao, F. Furnari, N. , and A. C. , PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth, Mol. Cell, vol.18, pp.13-24, 2005.

X. García-del-muro, A. López-pousa, J. Maurel, J. Martín, J. Martínez-trufero et al., Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.29, pp.2528-2533, 2011.

J. Garcia-donas, C. Rodriguez-antona, J. , and E. , Molecular markers to predict response to therapy, Semin. Oncol, vol.40, pp.444-458, 2013.
DOI : 10.1053/j.seminoncol.2013.05.005

J. M. García-martínez, A. , and D. R. , mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum-and glucocorticoid-induced protein kinase 1 (SGK1), Biochem. J, vol.416, pp.375-385, 2008.

S. George, Q. Wang, M. C. Heinrich, C. L. Corless, M. Zhu et al., Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.30, pp.2401-2407, 2012.

J. Gil, A. Stembalska, K. A. Pesz, and M. M. Sasiadek, Cancer stem cells: the theory and perspectives in cancer therapy, J. Appl. Genet, vol.49, pp.193-199, 2008.

A. C. Gingras, B. Raught, S. P. Gygi, A. Niedzwiecka, M. Miron et al., , 2001.

, Hierarchical phosphorylation of the translation inhibitor 4E-BP1, Genes Dev, vol.15, pp.2852-2864

J. R. Goldblum, A. L. Folpe, S. W. Weiss, F. M. Enzinger, and S. W. Weiss, Enzinger and Weiss's soft tissue tumors, 2014.

A. Gomez-pinillos and A. C. Ferrari, mTOR signaling pathway and mTOR inhibitors in cancer therapy, Hematol. Oncol. Clin. North Am, vol.26, pp.483-505, 2012.

A. M. Gonzalez-angulo, D. Juric, G. Argilés, J. H. Schellens, H. A. Burris et al., Safety, pharmacokinetics, and preliminary activity of the ?-specific PI3K inhibitor BYL719: Results from the first-in-human study, J. Clin. Oncol, vol.31, pp.2531-2531, 2013.

A. K. Gopal, B. S. Kahl, S. De-vos, N. D. Wagner-johnston, S. J. Schuster et al., PI3K? inhibition by idelalisib in patients with relapsed indolent lymphoma, N. Engl. J. Med, vol.370, pp.1008-1018, 2014.

W. T. Van-der-graaf, J. Blay, S. P. Chawla, D. Kim, B. Bui-nguyen et al., Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, Lancet Lond. Engl, vol.379, pp.1879-1886, 2012.

R. Grimer, I. Judson, D. Peake, and B. Seddon, Guidelines for the Management of Soft Tissue Sarcomas, 2010.

A. Gronchi, R. Miceli, E. Shurell, F. C. Eilber, F. R. Eilber et al., Outcome prediction in primary resected retroperitoneal soft tissue sarcoma: histology-specific overall survival and disease-free survival nomograms built on major sarcoma center data sets, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.31, pp.1649-1655, 2013.

A. Gronchi, D. C. Strauss, R. Miceli, S. Bonvalot, C. J. Swallow et al., Variability in Patterns of Recurrence After Resection of Primary Retroperitoneal Sarcoma, p.1007, 2016.

, Patients From the Multi-institutional Collaborative RPS Working Group, Ann. Surg, vol.263, pp.1002-1009

D. A. Guertin, D. M. Stevens, C. C. Thoreen, A. A. Burds, N. Y. Kalaany et al., Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1, Dev. Cell, vol.11, pp.859-871, 2006.

L. Guillou, A. , and A. , Soft tissue sarcomas with complex genomic profiles, Virchows Arch. Int. J. Pathol, vol.456, pp.201-217, 2010.
DOI : 10.1007/s00428-009-0853-4
URL : http://doc.rero.ch/record/312596/files/428_2009_Article_853.pdf

M. F. Gulen, K. Bulek, H. Xiao, M. Yu, J. Gao et al., Inactivation of the enzyme GSK3? by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates interleukin-1-induced Th17 cell maintenance, Immunity, vol.37, pp.800-812, 2012.

H. Guo, M. Gao, Y. Lu, J. Liang, P. L. Lorenzi et al., Coordinate phosphorylation of multiple residues on single AKT1 and AKT2 molecules, Oncogene, vol.33, pp.3463-3472, 2014.
DOI : 10.1038/onc.2013.301
URL : http://europepmc.org/articles/pmc3915040?pdf=render

S. Gupta, A. R. Ramjaun, P. Haiko, Y. Wang, P. H. Warne et al., Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice, Cell, vol.129, pp.957-968, 2007.

D. M. Gwinn, D. B. Shackelford, D. F. Egan, M. M. Mihaylova, A. Mery et al., AMPK phosphorylation of raptor mediates a metabolic checkpoint, Mol. Cell, vol.30, pp.214-226, 2008.

S. Hager, F. Makowiec, K. Henne, U. T. Hopt, and U. A. Wittel, Significant benefits in survival by the use of surgery combined with radiotherapy for retroperitoneal soft tissue sarcoma, Radiat. Oncol. Lond. Engl, vol.12, p.29, 2017.

M. Hanada, J. Feng, and B. A. Hemmings, Structure, regulation and function of PKB/AKT-a major therapeutic target, Biochim. Biophys. Acta, vol.1697, pp.3-16, 2004.

H. Hayashi, Y. Tsuchiya, K. Nakayama, T. Satoh, and E. Nishida, Down-regulation of the PI3-kinase/Akt pathway by ERK MAP kinase in growth factor signaling, Genes Cells Devoted Mol. Cell. Mech, vol.13, pp.941-947, 2008.

C. Hegedüs, K. Truta-feles, G. Antalffy, A. Brózik, I. Kasza et al., PI3-kinase and mTOR inhibitors differently modulate the function of the ABCG2 multidrug transporter, Biochem. Biophys. Res. Commun, vol.420, pp.869-874, 2012.

C. D. Helgason, C. P. Kalberer, J. E. Damen, S. M. Chappel, N. Pineault et al., A dual role for Src homology 2 domain-containing inositol-5phosphatase (SHIP) in immunity: aberrant development and enhanced function of b lymphocytes in ship-/-mice, J. Exp. Med, vol.191, pp.781-794, 2000.

J. D. Henson, J. A. Hannay, S. W. Mccarthy, J. A. Royds, T. R. Yeager et al., A robust assay for alternative lengthening of telomeres in tumors shows the significance of alternative lengthening of telomeres in sarcomas and astrocytomas, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.11, pp.217-225, 2005.

G. H. Heppner, Tumor heterogeneity, Cancer Res, vol.44, pp.2259-2265, 1984.

E. Hernando, E. Charytonowicz, M. E. Dudas, S. Menendez, I. Matushansky et al., The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas, Nat. Med, vol.13, pp.748-753, 2007.

I. Hers, E. E. Vincent, and J. M. Tavaré, Akt signalling in health and disease, Cell. Signal, vol.23, pp.1515-1527, 2011.
DOI : 10.1016/j.cellsig.2011.05.004

K. Hettinger, F. Vikhanskaya, M. K. Poh, M. K. Lee, I. De-belle et al., c-Jun promotes cellular survival by suppression of PTEN, Cell Death Differ, vol.14, pp.218-229, 2007.

H. Hirai, H. Sootome, Y. Nakatsuru, K. Miyama, S. Taguchi et al., MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo, Mol. Cancer Ther, vol.9, pp.1956-1967, 2010.
DOI : 10.1158/1535-7163.mct-09-1012
URL : http://mct.aacrjournals.org/content/9/7/1956.full.pdf

V. A. Holst, J. M. Junkins-hopkins, and R. Elenitsas, Cutaneous smooth muscle neoplasms: clinical features, histologic findings, and treatment options, J. Am. Acad. Dermatol, vol.46, pp.491-494, 2002.
DOI : 10.1067/mjd.2002.121358

M. K. Holz, B. A. Ballif, S. P. Gygi, and J. Blenis, mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events, Cell, vol.123, pp.569-580, 2005.

C. Honoré, P. Méeus, E. Stoeckle, and S. Bonvalot, Soft tissue sarcoma in France in 2015: Epidemiology, classification and organization of clinical care, J. Visc. Surg, vol.152, pp.223-230, 2015.

J. Hu, U. N. Rao, S. Jasani, V. Khanna, K. Yaw et al., Loss of DNA copy number of 10q is associated with aggressive behavior of leiomyosarcomas: a comparative genomic hybridization study, Cancer Genet. Cytogenet, vol.161, pp.20-27, 2005.

J. Huang, C. C. Dibble, M. Matsuzaki, and B. D. Manning, The TSC1-TSC2 complex is required for proper activation of mTOR complex 2, Mol. Cell. Biol, vol.28, pp.4104-4115, 2008.

L. Huw, C. O'brien, A. Pandita, S. Mohan, J. M. Spoerke et al., Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer, vol.2, p.83, 2013.
DOI : 10.1038/oncsis.2013.46
URL : http://www.nature.com/oncsis/journal/v2/n12/pdf/oncsis201346a.pdf

M. Inaba, H. Kobayashi, Y. Sakurai, J. , and R. K. , Active efflux of daunorubicin and adriamycin in sensitive and resistant sublines of P388 leukemia, Cancer Res, vol.39, pp.2200-2203, 1979.

K. Inoki, Y. Li, T. Zhu, J. Wu, and K. Guan, TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling, Nat. Cell Biol, vol.4, pp.648-657, 2002.
DOI : 10.1038/ncb839

K. Inoki, Y. Li, T. Xu, and K. Guan, Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling, Genes Dev, vol.17, pp.1829-1834, 2003.
DOI : 10.1101/gad.1110003
URL : http://genesdev.cshlp.org/content/17/15/1829.full.pdf

A. Italiano, M. Toulmonde, E. Stoeckle, M. Kind, G. Kantor et al., Clinical outcome of leiomyosarcomas of vascular origin: comparison with leiomyosarcomas of other origin, Ann. Oncol. Off. J. Eur. Soc. Med. Oncol, vol.21, pp.1915-1921, 2010.

A. Italiano, M. Kind, E. Stoeckle, N. Jones, J. Coindre et al., , 2011.

, Temsirolimus in advanced leiomyosarcomas: patterns of response and correlation with the activation of the mammalian target of rapamycin pathway, Anticancer. Drugs, vol.22, pp.463-467

O. H. Iwenofu, R. D. Lackman, A. P. Staddon, D. G. Goodwin, H. M. Haupt et al., Phospho-S6 ribosomal protein: a potential new predictive sarcoma marker for targeted mTOR therapy, Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc, vol.21, pp.231-237, 2008.

E. Jacinto, R. Loewith, A. Schmidt, S. Lin, M. A. Rüegg et al., , 2004.

, Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive, Nat. Cell Biol, vol.6, pp.1122-1128

E. Jacinto, V. Facchinetti, D. Liu, N. Soto, S. Wei et al., SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity, Cell, vol.127, pp.125-137, 2006.

S. Jain, R. Xu, V. G. Prieto, L. , and P. , Molecular classification of soft tissue sarcomas and its clinical applications, Int. J. Clin. Exp. Pathol, vol.3, pp.416-429, 2010.

L. Jin, K. J. Hope, Q. Zhai, F. Smadja-joffe, D. et al., Targeting of CD44 eradicates human acute myeloid leukemic stem cells, Nat. Med, vol.12, pp.1167-1174, 2006.

D. Juric, P. Castel, M. Griffith, O. L. Griffith, H. H. Won et al., Convergent loss of PTEN leads to clinical resistance to a PI(3)K? inhibitor, Nature, vol.518, pp.240-244, 2015.

O. Kaidanovich-beilin and J. R. Woodgett, GSK-3: Functional Insights from, Cell Biology and Animal Models. Front. Mol. Neurosci, vol.4, p.40, 2011.

M. Katz, I. Amit, Y. , and Y. , Regulation of MAPKs by growth factors and receptor tyrosine kinases, Biochim. Biophys. Acta, vol.1773, pp.1161-1176, 2007.

K. Kawaguchi, Y. Oda, T. Saito, H. Yamamoto, S. Tamiya et al., Mechanisms of inactivation of the p16INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis, J. Pathol, vol.201, pp.487-495, 2003.

M. Keniry and R. Parsons, mTOR inhibition, the second generation: ATPcompetitive mTOR inhibitor initiates unexpected receptor tyrosine kinase-driven feedback loop, Cancer Discov, vol.1, pp.203-204, 2011.
DOI : 10.1158/2159-8290.cd-11-0157
URL : http://cancerdiscovery.aacrjournals.org/content/1/3/203.full.pdf

D. Kim and C. Eng, The promise of mTOR inhibitors in the treatment of colorectal cancer, Expert Opin. Investig. Drugs, vol.21, pp.1775-1788, 2012.

S. J. Kim, M. A. Destefano, W. J. Oh, C. Wu, N. M. Vega-cotto et al., mTOR complex 2 regulates proper turnover of insulin receptor substrate-1 via the ubiquitin ligase subunit Fbw8, Mol. Cell, vol.48, pp.875-887, 2012.
DOI : 10.1016/j.molcel.2012.09.029
URL : https://doi.org/10.1016/j.molcel.2012.09.029

Y. Kimura, T. Morita, K. Hayashi, T. Miki, and K. Sobue, Myocardin functions as an effective inducer of growth arrest and differentiation in human uterine leiomyosarcoma cells, Cancer Res, vol.70, pp.501-511, 2010.
DOI : 10.1158/0008-5472.can-09-1469
URL : http://cancerres.aacrjournals.org/content/canres/70/2/501.full.pdf

A. Kiyatkin, E. Aksamitiene, N. I. Markevich, N. M. Borisov, J. B. Hoek et al., Scaffolding protein Grb2-associated binder 1 sustains epidermal growth factorinduced mitogenic and survival signaling by multiple positive feedback loops, J. Biol. Chem, vol.281, pp.19925-19938, 2006.
DOI : 10.1074/jbc.m600482200
URL : http://europepmc.org/articles/pmc2312093?pdf=render

R. A. Kleinerman, C. Yu, M. P. Little, Y. Li, D. Abramson et al., Variation of second cancer risk by family history of retinoblastoma among longterm survivors, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.30, pp.950-957, 2012.

H. Klümpen, J. H. Beijnen, H. Gurney, and J. H. Schellens, Inhibitors of mTOR, The Oncologist, vol.15, pp.1262-1269, 2010.

S. Koren and M. Bentires-alj, Tackling Resistance to PI3K Inhibition by Targeting the Epigenome, Cancer Cell, vol.31, pp.616-618, 2017.
DOI : 10.1016/j.ccell.2017.04.010

S. Kraft and C. D. Fletcher, Atypical intradermal smooth muscle neoplasms: clinicopathologic analysis of 84 cases and a reappraisal of cutaneous "leiomyosarcoma, Am. J. Surg. Pathol, vol.35, pp.599-607, 2011.

H. Kurosu, T. Maehama, T. Okada, T. Yamamoto, S. Hoshino et al., Heterodimeric phosphoinositide 3-kinase consisting of p85 and p110beta is synergistically activated by the betagamma subunits of G proteins and phosphotyrosyl peptide, J. Biol. Chem, vol.272, pp.24252-24256, 1997.

D. Lake, S. A. Corrêa, and J. Müller, Negative feedback regulation of the ERK1/2 MAPK pathway, Cell. Mol. Life Sci. CMLS, vol.73, pp.4397-4413, 2016.
DOI : 10.1007/s00018-016-2297-8
URL : https://link.springer.com/content/pdf/10.1007%2Fs00018-016-2297-8.pdf

G. K. Lakhanpal, L. M. Vecchiarelli-federico, Y. Li, J. Cui, M. L. Bailey et al., The inositol phosphatase SHIP1 is negatively regulated by Fli-1 and its loss accelerates leukemogenesis, Blood, vol.116, pp.428-436, 2010.
DOI : 10.1182/blood-2009-10-250217
URL : http://www.bloodjournal.org/content/bloodjournal/116/3/428.full.pdf

M. Laplante and D. M. Sabatini, An emerging role of mTOR in lipid biosynthesis, Curr. Biol. CB, vol.19, pp.1046-1052, 2009.

M. L. Larramendy, S. Kaur, C. Svarvar, T. Böhling, and S. Knuutila, Gene copy number profiling of soft-tissue leiomyosarcomas by array-comparative genomic hybridization, Cancer Genet. Cytogenet, vol.169, pp.94-101, 2006.

W. B. Laskin, J. C. Fanburg-smith, A. P. Burke, E. Kraszewska, J. F. Fetsch et al., Leiomyosarcoma of the inferior vena cava: clinicopathologic study of 40 cases, Am. J. Surg. Pathol, vol.34, pp.873-881, 2010.

X. Le, R. Antony, P. Razavi, D. J. Treacy, F. Luo et al., Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer, Cancer Discov, vol.6, pp.1134-1147, 2016.

A. Le-cesne, R. , and P. , Optimizing the use of trabectedin for advanced soft tissue sarcoma in daily clinical practice, Future Oncol. Lond. Engl, vol.11, pp.3-14, 2015.

A. Le-cesne, S. Cresta, R. G. Maki, J. Y. Blay, J. Verweij et al., A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas, Eur. J. Cancer Oxf. Engl, vol.48, pp.3036-3044, 1990.
URL : https://hal.archives-ouvertes.fr/hal-01057829

C. Lee, C. Yu, B. Wang, C. , and W. , Tumorsphere as an effective in vitro platform for screening anti-cancer stem cell drugs, Oncotarget, vol.7, pp.1215-1226, 2015.
DOI : 10.18632/oncotarget.6261
URL : http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=6261&path%5B%5D=16196

E. S. Lee, J. Locker, M. Nalesnik, J. Reyes, R. Jaffe et al., The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation, N. Engl. J. Med, vol.332, pp.19-25, 1995.

M. Lee, M. Jeong, H. Lee, H. Han, A. Ko et al., PI3K/AKT activation induces PTEN ubiquitination and destabilization accelerating tumourigenesis, Nat. Commun, vol.6, p.7769, 2015.

P. J. Lee, N. S. Yoo, I. S. Hagemann, J. D. Pfeifer, C. E. Cottrell et al., Spectrum of mutations in leiomyosarcomas identified by clinical targeted nextgeneration sequencing, Exp. Mol. Pathol, vol.102, pp.156-161, 2017.

S. Lee, K. Yang, J. Kwon, C. Lee, W. Jeong et al., Reversible inactivation of the tumor suppressor PTEN by H2O2, J. Biol. Chem, vol.277, pp.20336-20342, 2002.

B. Levine and G. Kroemer, Autophagy in the pathogenesis of disease, Cell, vol.132, pp.27-42, 2008.

X. Li and T. Gao, mTORC2 phosphorylates protein kinase C? to regulate its stability and activity, EMBO Rep, vol.15, pp.191-198, 2014.

C. Li, P. Xin, H. Xiao, Y. Zheng, Y. Huang et al., The dual PI3K/mTOR inhibitor NVP-BEZ235 inhibits proliferation and induces apoptosis of burkitt lymphoma cells, Cancer Cell Int, vol.15, p.65, 2015.

H. Li, X. Jin, Z. Zhang, Y. Xing, and X. Kong, Inhibition of autophagy enhances apoptosis induced by the PI3K/AKT/mTor inhibitor NVP-BEZ235 in renal cell carcinoma cells, Cell Biochem. Funct, vol.31, pp.427-433, 2013.

W. Li, M. Petrimpol, K. D. Molle, M. N. Hall, E. J. Battegay et al., , 2007.

, Hypoxia-induced endothelial proliferation requires both mTORC1 and mTORC2, Circ. Res, vol.100, pp.79-87

Z. Li, X. Dong, X. Dong, Z. Wang, W. Liu et al., Regulation of PTEN by Rho small GTPases, Nat. Cell Biol, vol.7, pp.399-404, 2005.

Y. Liao, H. , and M. , Physiological regulation of Akt activity and stability, Am. J. Transl. Res, vol.2, pp.19-42, 2010.

J. Liau, J. Tsai, Y. Jeng, J. Lee, H. Hsu et al., , 2015.

, Leiomyosarcoma with alternative lengthening of telomeres is associated with aggressive histologic features, loss of ATRX expression, and poor clinical outcome, Am. J. Surg. Pathol, vol.39, pp.236-244

P. Liu, W. Gan, H. Inuzuka, A. S. Lazorchak, D. Gao et al., Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis, Nat. Cell Biol, vol.15, pp.1340-1350, 2013.

P. Liu, M. Begley, W. Michowski, H. Inuzuka, M. Ginzberg et al., Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus, Nature, vol.508, pp.541-545, 2014.

P. Liu, W. Gan, Y. R. Chin, K. Ogura, J. Guo et al., PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase Complex, Cancer Discov, vol.5, pp.1194-1209, 2015.

M. C. Lorenz and J. Heitman, TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin, J. Biol. Chem, vol.270, pp.27531-27537, 1995.

J. Lu, H. Jeong, H. Jeong, N. Kong, Y. Yang et al., Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex, PloS One, vol.4, p.5577, 2009.

T. J. Lynch, D. W. Bell, R. Sordella, S. Gurubhagavatula, R. A. Okimoto et al., Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib, N. Engl. J. Med, vol.350, pp.2129-2139, 2004.

H. Maccario, N. M. Perera, A. Gray, C. P. Downes, L. et al., Ubiquitination of PTEN (phosphatase and tensin homolog) inhibits phosphatase activity and is enhanced by membrane targeting and hyperosmotic stress, J. Biol. Chem, vol.285, pp.12620-12628, 2010.

T. Maehama and J. E. Dixon, The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate, J. Biol. Chem, vol.273, pp.13375-13378, 1998.
DOI : 10.1074/jbc.273.22.13375
URL : http://www.jbc.org/content/273/22/13375.full.pdf

Y. Maeno, Q. Li, K. Park, C. Rask-madsen, B. Gao et al., Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K), J. Biol. Chem, vol.287, pp.4518-4530, 2012.

U. Maier, A. Babich, and B. Nürnberg, Roles of non-catalytic subunits in gbetagamma-induced activation of class I phosphoinositide 3-kinase isoforms beta and gamma, J. Biol. Chem, vol.274, pp.29311-29317, 1999.

S. Maira, F. Stauffer, J. Brueggen, P. Furet, C. Schnell et al., Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity, Mol. Cancer Ther, vol.7, pp.1851-1863, 2008.

S. Maira, S. Pecchi, A. Huang, M. Burger, M. Knapp et al., Identification and characterization of NVPBKM120, an orally available pan-class I PI3-kinase inhibitor, Mol. Cancer Ther, vol.11, pp.317-328, 2012.
DOI : 10.1158/1535-7163.mct-11-0474
URL : http://mct.aacrjournals.org/content/molcanther/11/2/317.full.pdf

P. K. Majumder, P. G. Febbo, R. Bikoff, R. Berger, Q. Xue et al., mTOR inhibition reverses Aktdependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1dependent pathways, Nat. Med, vol.10, pp.594-601, 2004.
DOI : 10.1038/nm1052

B. D. Manning and L. C. Cantley, AKT/PKB signaling: navigating downstream, Cell, vol.129, pp.1261-1274, 2007.
DOI : 10.1016/j.cell.2007.06.009
URL : https://doi.org/10.1016/j.cell.2007.06.009

B. D. Manning and A. Toker, AKT/PKB Signaling: Navigating the Network, Cell, vol.169, pp.381-405, 2017.
DOI : 10.1016/j.cell.2017.04.001
URL : http://europepmc.org/articles/pmc5546324?pdf=render

M. Mao, Y. Liu, and X. Gao, Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells, Biochem. Biophys. Res. Commun, vol.490, pp.1244-1249, 2017.

R. Marone, V. Cmiljanovic, B. Giese, and M. P. Wymann, Targeting phosphoinositide 3-kinase: moving towards therapy, Biochim. Biophys. Acta, vol.1784, pp.159-185, 2008.
DOI : 10.1016/j.bbapap.2007.10.003

J. L. Martin and R. C. Baxter, Expression of insulin-like growth factor binding protein-2 by MCF-7 breast cancer cells is regulated through the phosphatidylinositol 3kinase/AKT/mammalian target of rapamycin pathway, Endocrinology, vol.148, pp.2532-2541, 2007.

L. Martin, F. André, M. Campone, T. Bachelot, J. et al., mTOR inhibitors in advanced breast cancer: ready for prime time?, Cancer Treat. Rev, vol.39, pp.742-752, 2013.
DOI : 10.1016/j.ctrv.2013.02.005

C. Massard, K. N. Chi, D. Castellano, J. De-bono, G. Gravis et al., Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer, Eur. J. Cancer Oxf. Engl, vol.76, pp.36-44, 1990.

K. Masui, K. Tanaka, D. Akhavan, I. Babic, B. Gini et al., mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc, Cell Metab, vol.18, pp.726-739, 2013.

J. Mateo, G. Ganji, C. Lemech, H. A. Burris, S. Han et al., A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, 2017.

K. J. Mavrakis, A. L. Wolfe, E. Oricchio, T. Palomero, K. De-keersmaecker et al., Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia, Nat. Cell Biol, vol.12, pp.372-379, 2010.
DOI : 10.1038/ncb2037
URL : http://europepmc.org/articles/pmc2989719?pdf=render

K. L. Mcclain, C. T. Leach, H. B. Jenson, V. V. Joshi, B. H. Pollock et al., Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS, N. Engl. J. Med, vol.332, pp.12-18, 1995.

M. Mehrpour, A. Esclatine, I. Beau, C. , and P. , Overview of macroautophagy regulation in mammalian cells, Cell Res, vol.20, pp.748-762, 2010.

F. Meng, R. Henson, H. Wehbe-janek, K. Ghoshal, S. T. Jacob et al., , 2007.

, MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer, Gastroenterology, vol.133, pp.647-658

L. A. Meza-zepeda, S. H. Kresse, A. H. Barragan-polania, B. Bjerkehagen, H. O. Ohnstad et al., Array Comparative Genomic Hybridization Reveals Distinct DNA Copy Number Differences between Gastrointestinal Stromal Tumors and Leiomyosarcomas, Cancer Res, vol.66, pp.8984-8993, 2006.
DOI : 10.1158/0008-5472.can-06-1972

M. Miettinen and J. F. Fetsch, Evaluation of biological potential of smooth muscle tumours, Histopathology, vol.48, pp.97-105, 2006.
DOI : 10.1111/j.1365-2559.2005.02292.x

S. Z. Millis, S. Ikeda, S. Reddy, Z. Gatalica, and R. Kurzrock, Landscape of Phosphatidylinositol-3-Kinase Pathway Alterations Across 19 784 Diverse Solid Tumors, JAMA Oncol, vol.2, pp.1565-1573, 2016.
DOI : 10.1001/jamaoncol.2016.0891
URL : http://oncology.jamanetwork.com/data/journals/oncology/935919/coi160022.pdf

K. Miyajima, Y. Oda, S. Tamiya, K. Shimizu, Y. Hachitanda et al., , 2003.

, Cytogenetic and clinicopathological analysis of soft-tissue leiomyosarcomas, Pathol. Int, vol.53, pp.163-168

J. C. Mountford, Human embryonic stem cells: origins, characteristics and potential for regenerative therapy, Transfus. Med. Oxf. Engl, vol.18, pp.1-12, 2008.

Y. Nakanishi, K. Walter, J. M. Spoerke, C. O'brien, L. Y. Huw et al., Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110?, Cancer Res, vol.76, pp.1193-1203, 2016.

A. Neuville, D. Ranchère-vince, A. P. Dei-tos, M. C. Montesco, I. Hostein et al., Impact of molecular analysis on the final sarcoma diagnosis: a study on 763 cases collected during a European epidemiological study, Am. J. Surg. Pathol, vol.37, pp.1259-1268, 2013.

H. Nojima, C. Tokunaga, S. Eguchi, N. Oshiro, S. Hidayat et al., The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif, J. Biol. Chem, vol.278, pp.15461-15464, 2003.

N. Nungaray, M. Arriola, M. J. Gutierrez, E. Oliva, E. Hernández et al., Rapamycin at Six Years Can Exhibit Normal Renal Function Without Proteinuria or Neoplasia After Renal Transplantation. A Single-Center Experience, Transplant. Proc, vol.37, pp.3727-3728, 2005.

D. P. Nussbaum, C. N. Rushing, W. O. Lane, D. M. Cardona, D. G. Kirsch et al., Preoperative or postoperative radiotherapy versus surgery alone for retroperitoneal sarcoma: a case-control, propensity score-matched analysis of a nationwide clinical oncology database, Lancet Oncol, vol.17, pp.966-975, 2016.

H. Nyström, M. Jönsson, L. Werner-hartman, M. Nilbert, C. et al., , 2017.

, Hypoxia-inducible factor 1? predicts recurrence in high-grade soft tissue sarcoma of extremities and trunk wall, J. Clin. Pathol

C. A. O'brien, A. Kreso, and C. H. Jamieson, Cancer stem cells and self-renewal, 2010.

, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.16, pp.3113-3120

D. O'carroll, S. Erhardt, M. Pagani, S. C. Barton, M. A. Surani et al., , 2001.

, The polycomb-group gene Ezh2 is required for early mouse development, Mol. Cell. Biol, vol.21, pp.4330-4336

K. Okumura, M. Mendoza, R. M. Bachoo, R. A. Depinho, W. K. Cavenee et al., PCAF modulates PTEN activity, J. Biol. Chem, vol.281, pp.26562-26568, 2006.

C. Oliveras-ferraros, A. Vazquez-martin, E. Cuyàs, B. Corominas-faja, E. Rodríguezgallego et al., , 2014.

, Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile, Cell Cycle Georget. Tex, vol.13, pp.1132-1144

Y. Onishi-haraikawa, M. Funaki, N. Gotoh, M. Shibuya, K. Inukai et al., Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein, Biochem. Biophys. Res. Commun, vol.288, pp.476-482, 2001.

M. H. Orme, S. Alrubaie, G. L. Bradley, C. D. Walker, and S. J. Leevers, Input from Ras is required for maximal PI(3)K signalling in Drosophila, Nat. Cell Biol, vol.8, pp.1298-1302, 2006.
DOI : 10.1038/ncb1493

M. E. Pacold, S. Suire, O. Perisic, S. Lara-gonzalez, C. T. Davis et al., Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma, Cell, vol.103, pp.931-943, 2000.
DOI : 10.1016/s0092-8674(00)00196-3
URL : https://doi.org/10.1016/s0092-8674(00)00196-3

I. Panagopoulos, C. Lassen, M. Isaksson, F. Mitelman, N. Mandahl et al., Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia, Oncogene, vol.15, pp.1357-1362, 1997.

K. P. Papadopoulos, C. Egile, R. Ruiz-soto, J. Jiang, W. Shi et al., Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: a phase 1 expansion cohort in patients with relapsed or refractory lymphoma, Leuk. Lymphoma, vol.56, pp.1763-1770, 2015.

I. T. Paulsen, J. H. Park, P. S. Choi, and M. H. Saier, A family of gram-negative bacterial outer membrane factors that function in the export of proteins, carbohydrates, drugs and heavy metals from gram-negative bacteria, FEMS Microbiol. Lett, vol.156, pp.1-8, 1997.

P. Pautier, A. Floquet, N. Penel, S. Piperno-neumann, N. Isambert et al., Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarcoma Group Study (TAXOGEM study), The Oncologist, vol.17, pp.1213-1220, 2012.

L. R. Pearce, D. Komander, A. , and D. R. , The nuts and bolts of AGC protein kinases, Nat. Rev. Mol. Cell Biol, vol.11, pp.9-22, 2010.
DOI : 10.1038/nrm2822

A. Pemov, H. Li, R. Patidar, N. F. Hansen, S. Sindiri et al., The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas, Oncogene, vol.36, pp.3168-3177, 2017.

G. Pérot, J. Derré, J. Coindre, F. Tirode, C. Lucchesi et al., Strong smooth muscle differentiation is dependent on myocardin gene amplification in most human retroperitoneal leiomyosarcomas, Cancer Res, vol.69, pp.2269-2278, 2009.

G. Pérot, F. Chibon, A. Montero, P. Lagarde, H. De-thé et al., Constant p53 Pathway Inactivation in a Large Series of Soft Tissue Sarcomas with Complex Genetics, Am. J. Pathol, vol.177, pp.2080-2090, 2010.

R. T. Peterson and S. L. Schreiber, Kinase phosphorylation: Keeping it all in the family, Curr. Biol. CB, vol.9, pp.521-524, 1999.
DOI : 10.1016/s0960-9822(99)80326-1
URL : https://doi.org/10.1016/s0960-9822(99)80326-1

T. R. Peterson, M. Laplante, C. C. Thoreen, Y. Sancak, S. A. Kang et al., DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival, Cell, vol.137, pp.873-886, 2009.
DOI : 10.1016/j.cell.2009.03.046
URL : https://doi.org/10.1016/j.cell.2009.03.046

K. G. Pike, K. Malagu, M. G. Hummersone, K. A. Menear, H. M. Duggan et al., Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: the discovery of AZD8055 and AZD2014, Bioorg. Med. Chem. Lett, vol.23, pp.1212-1216, 2013.

G. Pintus, B. Tadolini, A. M. Posadino, B. Sanna, M. Debidda et al., Inhibition of the MEK/ERK signaling pathway by the novel antimetastatic agent NAMI-A down regulates c-myc gene expression and endothelial cell proliferation, Eur. J. Biochem, vol.269, pp.5861-5870, 2002.

L. Poulain, P. Sujobert, F. Zylbersztejn, S. Barreau, L. Stuani et al., High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells, Leukemia, 2017.
DOI : 10.1038/leu.2017.81

A. Puissant, N. Fenouille, A. , and P. , When autophagy meets cancer through p62/SQSTM1, Am. J. Cancer Res, vol.2, pp.397-413, 2012.

B. K. Ragon, H. Kantarjian, E. Jabbour, F. Ravandi, J. Cortes et al., Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I trial of patients with advanced leukemias, Am. J. Hematol, vol.92, pp.7-11, 2017.

A. Ramanathan and S. L. Schreiber, Direct control of mitochondrial function by mTOR, Proc. Natl. Acad. Sci. U. S. A, vol.106, pp.22229-22232, 2009.

J. W. Ramos, The regulation of extracellular signal-regulated kinase (ERK) in mammalian cells, Int. J. Biochem. Cell Biol, vol.40, pp.2707-2719, 2008.

F. J. Ramos, M. Kaeberlein, K. , and B. K. , Elevated MTORC1 signaling and impaired autophagy, Autophagy, vol.9, pp.108-109, 2013.
DOI : 10.4161/auto.22401
URL : http://www.tandfonline.com/doi/pdf/10.4161/auto.22401?needAccess=true

E. Raymond, J. Alexandre, S. Faivre, K. Vera, E. Materman et al., Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.22, pp.2336-2347, 2004.

R. D. Read, W. K. Cavenee, F. B. Furnari, T. , and J. B. , A drosophila model for EGFR-Ras and PI3K-dependent human glioma, PLoS Genet, vol.5, 2009.
DOI : 10.1371/journal.pgen.1000374
URL : https://doi.org/10.1371/journal.pgen.1000374

P. Reichardt, G. D. Demetri, H. Gelderblom, P. Rutkowski, S. Im et al., Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial, BMC Cancer, vol.16, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01800022

Y. Robin, N. Penel, G. Pérot, A. Neuville, V. Vélasco et al., Transgelin is a novel marker of smooth muscle differentiation that improves diagnostic accuracy of leiomyosarcomas: a comparative immunohistochemical reappraisal of myogenic markers in 900 soft tissue tumors, Mod. Pathol, vol.26, pp.502-510, 2013.

J. Rodon, R. Dienstmann, V. Serra, and J. Tabernero, Development of PI3K inhibitors: lessons learned from early clinical trials, Nat. Rev. Clin. Oncol, vol.10, pp.143-153, 2013.
DOI : 10.1038/nrclinonc.2013.10

M. Rosemann, I. Gonzalez-vasconcellos, T. Domke, V. Kuosaite, R. Schneider et al., A Rb1 promoter variant with reduced activity contributes to osteosarcoma susceptibility in irradiated mice, Mol. Cancer, vol.13, p.182, 2014.
DOI : 10.1186/1476-4598-13-182
URL : https://molecular-cancer.biomedcentral.com/track/pdf/10.1186/1476-4598-13-182

P. P. Roux, B. A. Ballif, R. Anjum, S. P. Gygi, and J. Blenis, Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase, Proc. Natl. Acad. Sci. U. S. A, vol.101, pp.13489-13494, 2004.
DOI : 10.1073/pnas.0405659101
URL : http://europepmc.org/articles/pmc518784?pdf=render

C. J. Sabers, M. M. Martin, G. J. Brunn, J. M. Williams, F. J. Dumont et al., Isolation of a Protein Target of the FKBP12-Rapamycin Complex in Mammalian Cells, J. Biol. Chem, vol.270, pp.815-822, 1995.

K. S. Saini, S. Loi, E. De-azambuja, O. Metzger-filho, M. L. Saini et al., Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer, Cancer Treat. Rev, vol.39, pp.935-946, 2013.

L. Salphati, L. B. Lee, J. Pang, E. G. Plise, and X. Zhang, Role of P-glycoprotein and breast cancer resistance protein-1 in the brain penetration and brain pharmacodynamic activity of the novel phosphatidylinositol 3-kinase inhibitor GDC-0941, Drug Metab. Dispos. Biol. Fate Chem, vol.38, pp.1422-1426, 2010.

T. Sangai, A. Akcakanat, H. Chen, E. Tarco, Y. Wu et al., Biomarkers of response to Akt inhibitor MK-2206 in breast cancer, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.18, pp.5816-5828, 2012.

D. D. Sarbassov, D. A. Guertin, S. M. Ali, and D. M. Sabatini, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex, Science, vol.307, pp.1098-1101, 2005.
DOI : 10.1126/science.1106148

D. Sarker, J. E. Ang, R. Baird, R. Kristeleit, K. Shah et al., First-in-human phase I study of pictilisib (GDC0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.21, pp.77-86, 2015.

C. Saura, D. Roda, S. Roselló, M. Oliveira, T. Macarulla et al., A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid Tumors, Cancer Discov, vol.7, pp.102-113, 2017.

M. Savina, A. Le-cesne, J. Blay, I. Ray-coquard, O. Mir et al., Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study, BMC Med, vol.15, p.78, 2017.

R. A. Saxton and D. M. Sabatini, mTOR Signaling in Growth, Metabolism, and Disease, vol.168, pp.960-976, 2017.
DOI : 10.1016/j.cell.2017.02.004
URL : http://europepmc.org/articles/pmc5394987?pdf=render

E. D. Scheeff and P. E. Bourne, Structural evolution of the protein kinase-like superfamily, PLoS Comput. Biol, vol.1, p.49, 2005.

S. Schubbert, K. Shannon, and G. Bollag, Hyperactive Ras in developmental disorders and cancer, Nat. Rev. Cancer, vol.7, pp.295-308, 2007.
DOI : 10.1038/nrc2109

R. Sears, F. Nuckolls, E. Haura, Y. Taya, K. Tamai et al., Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability, Genes Dev, vol.14, pp.2501-2514, 2000.
DOI : 10.1101/gad.836800
URL : http://genesdev.cshlp.org/content/14/19/2501.full.pdf

E. Seront, S. Rottey, B. Filleul, P. Glorieux, J. Goeminne et al., Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma, BJU Int, vol.118, pp.408-415, 2016.

N. Setsu, H. Yamamoto, K. Kohashi, M. Endo, S. Matsuda et al., The Akt/mammalian target of rapamycin pathway is activated and associated with adverse prognosis in soft tissue leiomyosarcomas, Cancer, vol.118, pp.1637-1648, 2012.

G. I. Shapiro, J. Rodon, C. Bedell, E. L. Kwak, J. Baselga et al., Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.20, pp.233-245, 2014.

W. H. Shen, A. S. Balajee, J. Wang, H. Wu, C. Eng et al., , 2007.

, Essential role for nuclear PTEN in maintaining chromosomal integrity, Cell, vol.128, pp.157-170

C. J. Sherr and F. Mccormick, The RB and p53 pathways in cancer, Cancer Cell, vol.2, pp.103-112, 2002.

Y. Shi, B. E. Paluch, X. Wang, J. , and X. , PTEN at a glance, J. Cell Sci, vol.125, pp.4687-4692, 2012.

E. K. Shim, S. H. Jung, and J. R. Lee, Role of two adaptor molecules SLP-76 and LAT in the PI3K signaling pathway in activated T cells, J. Immunol. Baltim. Md, vol.186, pp.2926-2935, 1950.

T. Shimizu, A. W. Tolcher, K. P. Papadopoulos, M. Beeram, D. W. Rasco et al., The clinical effect of the dualtargeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.18, pp.2316-2325, 2012.

S. Shin, O. Rath, A. Zebisch, S. Choo, W. Kolch et al., Functional roles of multiple feedback loops in extracellular signal-regulated kinase and Wnt signaling pathways that regulate epithelial-mesenchymal transition, Cancer Res, vol.70, pp.6715-6724, 2010.

N. Sirvent, J. Coindre, G. Maire, I. Hostein, F. Keslair et al., Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR, Am. J. Surg. Pathol, vol.31, pp.1476-1489, 2007.

M. W. Sleeman, K. E. Wortley, K. V. Lai, L. C. Gowen, J. Kintner et al., Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity, Nat. Med, vol.11, pp.199-205, 2005.

M. Slimane, N. B. Yahia, H. Bouaziz, H. Bouzaine, J. Benhassouna et al., Inferior vena cava leiomyosarcoma: vascular reconstruction is not always mandatory, Pan Afr. Med. J, vol.24, p.287, 2016.

L. M. Smith, A. Nesterova, M. C. Ryan, S. Duniho, M. Jonas et al., CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers, Br. J. Cancer, vol.99, pp.100-109, 2008.

H. P. Soares, M. Ming, M. Mellon, S. H. Young, L. Han et al., Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2, Mol. Cancer Ther, vol.14, pp.1014-1023, 2015.

M. S. Song, L. Salmena, and P. P. Pandolfi, The functions and regulation of the PTEN tumour suppressor, Nat. Rev. Mol. Cell Biol, vol.13, pp.283-296, 2012.

F. Stauffer, C. Garcia-echeverria, P. Furet, C. Schnell, S. Ruetz et al., Biochemical, cellular and in vivo profiling of a new PI3K inhibitor from the imidazoquinoline series, Cancer Res, vol.67, pp.269-269, 2007.

L. R. Stephens, A. Eguinoa, H. Erdjument-bromage, M. Lui, F. Cooke et al., The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101, Cell, vol.89, pp.105-114, 1997.

C. A. Stiller, A. Trama, D. Serraino, S. Rossi, C. Navarro et al., Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project, Eur. J. Cancer Oxf. Engl, vol.49, pp.684-695, 1990.

R. W. Storms, A. P. Trujillo, J. B. Springer, L. Shah, O. M. Colvin et al., Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity, Proc. Natl. Acad. Sci. U. S. A, vol.96, pp.9118-9123, 1999.

M. R. Stratton, S. Williams, C. Fisher, A. Ball, G. Westbury et al., Structural alterations of the RB1 gene in human soft tissue tumours, Br. J. Cancer, vol.60, pp.202-205, 1989.

Y. Sun, Y. Jiang, J. Huang, H. Chen, Y. Liao et al., CISD2 enhances the chemosensitivity of gastric cancer through the enhancement of 5-FU-induced apoptosis and the inhibition of autophagy by AKT/mTOR pathway, Cancer Med, 2017.

M. Suvà, N. Riggi, J. Stehle, K. Baumer, S. Tercier et al., Identification of cancer stem cells in Ewing's sarcoma, Cancer Res, vol.69, pp.1776-1781, 2009.

G. Szakács, J. K. Paterson, J. A. Ludwig, C. Booth-genthe, and M. M. Gottesman, Targeting multidrug resistance in cancer, Nat. Rev. Drug Discov, vol.5, pp.219-234, 2006.

M. S. Tallman, C. Nabhan, J. H. Feusner, R. , and J. M. , Acute promyelocytic leukemia: evolving therapeutic strategies, Blood, vol.99, pp.759-767, 2002.
DOI : 10.1182/blood.v99.3.759
URL : http://www.bloodjournal.org/content/99/3/759.full.pdf

M. Tamura, J. Gu, T. Takino, and K. M. Yamada, Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas, Cancer Res, vol.59, pp.442-449, 1999.

K. Tanaka, I. Babic, D. Nathanson, D. Akhavan, D. Guo et al., Oncogenic EGFR signaling activates an mTORC2-NF-?B pathway that promotes chemotherapy resistance, Cancer Discov, vol.1, pp.524-538, 2011.
DOI : 10.1158/2159-8290.cd-11-0124
URL : http://cancerdiscovery.aacrjournals.org/content/candisc/1/6/524.full.pdf

S. C. Tang, R. W. Sparidans, K. L. Cheung, T. Fukami, S. Durmus et al., P-glycoprotein, CYP3A, and plasma carboxylesterase determine brain and blood disposition of the mTOR Inhibitor everolimus (Afinitor) in mice, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res, vol.20, pp.3133-3145, 2014.

O. Tawfik, D. Rao, W. B. Nothnick, A. Graham, B. Mau et al., Transgelin, a Novel Marker of Smooth Muscle Differentiation, Effectively Distinguishes Endometrial Stromal Tumors from Uterine Smooth Muscle Tumors, Int. J. Gynecol. Obstet. Reprod. Med. Res, vol.1, pp.26-31, 2014.

D. T. Teachey, S. A. Grupp, and V. I. Brown, Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies, Br. J. Haematol, vol.145, pp.569-580, 2009.

S. Temraz, D. Mukherji, and A. Shamseddine, Dual Inhibition of MEK and PI3K Pathway in KRAS and BRAF Mutated Colorectal Cancers, Int. J. Mol. Sci, vol.16, pp.22976-22988, 2015.

V. Thomanetz, N. Angliker, D. Cloëtta, R. M. Lustenberger, M. Schweighauser et al., Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology, J. Cell Biol, vol.201, pp.293-308, 2013.

V. Tirino, V. Desiderio, F. Paino, A. De-rosa, F. Papaccio et al., Human primary bone sarcomas contain CD133+ cancer stem cells displaying high tumorigenicity in vivo, FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol, vol.25, pp.2022-2030, 2011.
DOI : 10.1096/fj.10-179036

A. Toker, N. , and A. C. , Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site, J. Biol. Chem, vol.275, pp.8271-8274, 2000.
DOI : 10.1074/jbc.275.12.8271
URL : http://www.jbc.org/content/275/12/8271.full.pdf

L. A. Torre, F. Bray, R. L. Siegel, J. Ferlay, J. Lortet-tieulent et al., Global cancer statistics, 2012. CA, Cancer J. Clin, vol.65, pp.87-108, 2015.
DOI : 10.3322/caac.21262

M. Trojani, G. Contesso, J. M. Coindre, J. Rouesse, N. B. Bui et al., Soft-tissue sarcomas of adults; study of pathological prognostic variables and definition of a histopathological grading system, Int. J. Cancer, vol.33, pp.37-42, 1984.

S. Tsukamoto, Y. Huang, D. Umeda, S. Yamada, S. Yamashita et al., 67-kDa laminin receptor-dependent protein phosphatase 2A (PP2A) activation elicits melanoma-specific antitumor activity overcoming drug resistance, J. Biol. Chem, vol.289, pp.32671-32681, 2014.
DOI : 10.1074/jbc.m114.604983
URL : http://www.jbc.org/content/289/47/32671.full.pdf

O. Vadas, J. E. Burke, X. Zhang, A. Berndt, W. et al., Structural basis for activation and inhibition of class I phosphoinositide 3-kinases, Sci. Signal, vol.4, p.2, 2011.

E. Vander-haar, S. Lee, S. Bandhakavi, T. J. Griffin, K. et al., Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40, Nat. Cell Biol, vol.9, pp.316-323, 2007.

B. Vanhaesebroeck, J. Guillermet-guibert, M. Graupera, and B. Bilanges, The emerging mechanisms of isoform-specific PI3K signalling, Nat. Rev. Mol. Cell Biol, vol.11, pp.329-341, 2010.

F. Vazquez, S. R. Grossman, Y. Takahashi, M. V. Rokas, N. Nakamura et al., Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex, J. Biol. Chem, vol.276, pp.48627-48630, 2001.

B. Vergès, T. Walter, C. , and B. , Endocrine side effects of anti-cancer drugs: effects of anti-cancer targeted therapies on lipid and glucose metabolism, Eur. J. Endocrinol, vol.170, pp.43-55, 2014.

E. Vilar, J. Perez-garcia, and J. Tabernero, Pushing the envelope in the mTOR pathway: the second generation of inhibitors, Mol. Cancer Ther, vol.10, pp.395-403, 2011.

I. Vivanco and C. L. Sawyers, The phosphatidylinositol 3-Kinase AKT pathway in human cancer, Nat. Rev. Cancer, vol.2, pp.489-501, 2002.

K. E. Van-der-vos and P. J. Coffer, The extending network of FOXO transcriptional target genes, Antioxid. Redox Signal, vol.14, pp.579-592, 2011.

E. H. Walker, M. E. Pacold, O. Perisic, L. Stephens, P. T. Hawkins et al., Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine, Mol. Cell, vol.6, pp.909-919, 2000.

D. Walter, S. Satheesha, P. Albrecht, B. C. Bornhauser, V. D'alessandro et al., CD133 positive embryonal rhabdomyosarcoma stem-like cell population is enriched in rhabdospheres, PloS One, vol.6, 2011.

L. Wang, P. Park, H. Zhang, F. La-marca, L. et al., Prospective identification of tumorigenic osteosarcoma cancer stem cells in OS99-1 cells based on high aldehyde dehydrogenase activity, Int. J. Cancer, vol.128, pp.294-303, 2011.

R. Wang, Y. J. Lu, C. Fisher, J. A. Bridge, and J. Shipley, Characterization of chromosome aberrations associated with soft-tissue leiomyosarcomas by twenty-four-color karyotyping and comparative genomic hybridization analysis, Genes. Chromosomes Cancer, vol.31, pp.54-64, 2001.

R. Wang, J. C. Titley, Y. Lu, B. M. Summersgill, J. A. Bridge et al., Loss of 13q14-q21 and gain of 5p14-pter in the progression of leiomyosarcoma, Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc, vol.16, pp.778-785, 2003.

A. E. Webb and A. Brunet, FOXO transcription factors: key regulators of cellular quality control, Trends Biochem. Sci, vol.39, pp.159-169, 2014.

M. Weiler, J. Blaes, S. Pusch, F. Sahm, M. Czabanka et al., mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy, Proc. Natl. Acad. Sci. U. S. A, vol.111, pp.409-414, 2014.

J. T. Whelan, S. L. Forbes, and F. E. Bertrand, CBF-1 (RBP-J kappa) binds to the PTEN promoter and regulates PTEN gene expression, Cell Cycle Georget. Tex, vol.6, pp.80-84, 2007.

E. J. White, V. Martin, J. Liu, S. R. Klein, S. Piya et al., Autophagy regulation in cancer development and therapy, Am. J. Cancer Res, vol.1, pp.362-372, 2011.

C. Wibmer, A. Leithner, N. Zielonke, M. Sperl, and R. Windhager, Increasing incidence rates of soft tissue sarcomas? A population-based epidemiologic study and literature review, Ann. Oncol, vol.21, pp.1106-1111, 2010.

C. Wu, C. Hsieh, and Y. Wu, The emergence of drug transporter-mediated multidrug resistance to cancer chemotherapy, Mol. Pharm, vol.8, 1996.

C. Wu, M. Murakami, S. Hsiao, A. Chou, Y. Li et al., Overexpression of ATP-Binding Cassette Subfamily G Member, 2017.

, Confers Resistance to Phosphatidylinositol 3-Kinase Inhibitor PF-4989216 in Cancer Cells, Mol. Pharm, vol.14, pp.2368-2377

L. Wu, Z. Feng, S. Cui, K. Hou, L. Tang et al., Rapamycin upregulates autophagy by inhibiting the mTOR-ULK1 pathway, resulting in reduced podocyte injury, PloS One, vol.8, p.63799, 2013.

Y. L. Wu, U. B. Maachani, M. Schweitzer, R. Singh, M. Wang et al., Dual Inhibition of PI3K/AKT and MEK/ERK Pathways Induces Synergistic Antitumor Effects in Diffuse Intrinsic Pontine Glioma Cells, Transl. Oncol, vol.10, pp.221-228, 2017.

D. Xia, H. Srinivas, Y. Ahn, G. Sethi, X. Sheng et al., Mitogen-activated protein kinase kinase-4 promotes cell survival by decreasing PTEN expression through an NF kappa B-dependent pathway, J. Biol. Chem, vol.282, pp.3507-3519, 2007.

C. Yang, J. Peng, W. Jiang, Y. Zhang, X. Chen et al., mTOR activation in immature cells of primary nasopharyngeal carcinoma and anti-tumor effect of rapamycin in vitro and in vivo, Cancer Lett, vol.341, pp.186-194, 2013.

G. Yang, D. S. Murashige, S. J. Humphrey, J. , and D. E. , A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation, Cell Rep, vol.12, pp.937-943, 2015.

H. Yang, D. G. Rudge, J. D. Koos, B. Vaidialingam, H. J. Yang et al., mTOR kinase structure, mechanism and regulation, Nature, vol.497, pp.217-223, 2013.

J. Yang, X. Du, K. Chen, A. Ylipää, A. J. Lazar et al., Genetic aberrations in soft tissue leiomyosarcoma, Cancer Lett, vol.275, pp.1-8, 2009.

T. A. Yap, L. Yan, A. Patnaik, I. Fearen, D. Olmos et al., First-in-man clinical trial of the oral panAKT inhibitor MK-2206 in patients with advanced solid tumors, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.29, pp.4688-4695, 2011.

N. A. Zeliadt, L. J. Mauro, and E. V. Wattenberg, Reciprocal regulation of extracellular signal regulated kinase 1/2 and mitogen activated protein kinase, p.3, 2008.

, Toxicol. Appl. Pharmacol, vol.232, pp.408-417

H. Zhang, N. Bajraszewski, E. Wu, H. Wang, A. P. Moseman et al., PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR, J. Clin. Invest, vol.117, pp.730-738, 2007.

Q. Zhang, J. Ubago, L. Li, H. Guo, Y. Liu et al., Molecular analyses of 6 different types of uterine smooth muscle tumors: Emphasis in atypical leiomyoma, Cancer, vol.120, pp.3165-3177, 2014.

S. Q. Zhang, W. G. Tsiaras, T. Araki, G. Wen, L. Minichiello et al., Receptor-specific regulation of phosphatidylinositol 3'-kinase activation by the protein tyrosine phosphatase Shp2, Mol. Cell. Biol, vol.22, pp.4062-4072, 2002.

X. Zhang, H. Yang, S. Yue, G. He, S. Qu et al., The mTOR inhibition in concurrence with ERK1/2 activation is involved in excessive autophagy induced by glycyrrhizin in hepatocellular carcinoma, Cancer Med, vol.6, pp.1941-1951, 2017.

Y. Zhu, T. Tian, J. Zou, Q. Wang, Z. Li et al., Dual PI3K/mTOR inhibitor BEZ235 exerts extensive antitumor activity in HER2positive gastric cancer, BMC Cancer, vol.15, p.894, 2015.

Y. Zhu, H. Min, J. Fang, F. Zhou, X. Deng et al., Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma, Cancer Biol. Ther, vol.16, pp.602-609, 2015.

S. Zimmermann and K. Moelling, Phosphorylation and regulation of Raf by Akt (protein kinase B), Science, vol.286, pp.1741-1744, 1999.

V. Zinzalla, D. Stracka, W. Oppliger, and M. N. Hall, Activation of mTORC2 by association with the ribosome, Cell, vol.144, pp.757-768, 2011.