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Implication de la sortiline dans la sensibilité aux thérapies ciblées dans le cancer bronchique

Abstract : Bronchial cancer remains the leading cause of cancer death worldwide due to lack of early diagnosis and difficulties of treatment. This failure of therapeutic strategies is mainly due to the presence of aberrant EGFR mutations and activations leading to exacerbated tumor growth. Despite the evolution and diversification of targeted therapies aimed at inactivating these receptors, the use of tyrosine kinase inhibitors targeting EGFR still shows an initial efficacy whose benefits decrease with time. One of the mechanisms of resistance explaining this phenomenon may depend on the switch between EGFR membrane and nuclear signaling. Indeed, the nuclear relocation of EGFR would induce the expression of genomic targets responsible for therapeutic escape and recurrence. Our previous work has already identified the original function of a transport protein, sortilin, in the inhibition of EGFR membrane signaling. However, the discovery of sortilin at the nuclear level highlights a new role for sortilin as a crucial regulator of nuclear EGFR-controlled oncogenes. A large panel of EGFR target genes controlled by sortilin could be characterized. Our work led us to analyze more specifically the action of sortilin on the expression of cMYC and CCND1. The latter would indeed induce a decrease in the recruitment of RNA pol II which is crucial for their transcription. During treatment with osimertinib, sortilin binding to chromatin is increased, leading to a repression of target genes such as cMYC. This suggests that sortilin may be a protein that represses the expression of target genes such as cMYC. Our transcriptomic analyses conducted on a cohort of patients confirmed the repressive effect of sortilin on the cMYC gene. These results open interesting perspectives for the diagnosis of NSCLC and the prediction of recurrence. In the future, sortilin could be a therapeutic agent allowing the resensitisation of tumors to treatment.
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Submitted on : Sunday, July 17, 2022 - 1:02:18 AM
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Eric Lapeyronnie. Implication de la sortiline dans la sensibilité aux thérapies ciblées dans le cancer bronchique. Médecine humaine et pathologie. Université de Limoges, 2021. Français. ⟨NNT : 2021LIMO0051⟩. ⟨tel-03725401⟩

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