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Les vulnérabilités métaboliques des cancers résistants au cisplatine

Florine Obrist 1
1 Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 - Apoptose, cancer et immunité
IGR - Institut Gustave Roussy, CRC - Centre de Recherche des Cordeliers
Abstract : Cisplatin is the most widely used chemotherapeutic agent, and resistance of neoplastic cells against this cytoxicant pose a major problem in clinical oncology. Here, we explored potential metabolic vulnerabilities of cisplatin-resistant non-small cell lung cancer and ovarian cancer cell lines. Cisplatin resistant clones were more sensitive to killing by nutrient deprivation in vitro and in vivo than their parental cisplatin-sensitive controls. The susceptibility of cisplatin-resistant cells to starvation could be explained by a particularly strong dependence on glutamine. Glutamine depletion was sufficient to restore cisplatin responses of initially cisplatin-resistant clones, and glutamine supplementation rescued cisplatin resistant clones from starvation-induced death. Mass spectrometric metabolomics and specific interventions on glutamine metabolism revealed that, in cisplatin-resistant cells, glutamine is mostly required for nucleotide biosynthesis rather than for anaplerotic, bioenergetic or redox reactions. As a result, cisplatin-resistant cancers became exquisitely sensitive to treatment with antimetabolites that target nucleoside metabolism.
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https://tel.archives-ouvertes.fr/tel-01806341
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  • HAL Id : tel-01806341, version 1

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Florine Obrist. Les vulnérabilités métaboliques des cancers résistants au cisplatine. Cancer. Université Paris-Saclay, 2017. Français. ⟨NNT : 2017SACLS571⟩. ⟨tel-01806341⟩

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