Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies - CNRS - Centre national de la recherche scientifique
Article Dans Une Revue Nature Communications Année : 2024

Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies

Irene Ferrer
Luis Paz-Ares
  • Fonction : Auteur
Linda Kessler
  • Fonction : Auteur
Francis Burrows
  • Fonction : Auteur

Résumé

Abstract Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we combine real-time monitoring of the cell-cycle dynamics and single-cell RNA sequencing in a broad panel of oncogenic addiction such as EGFR-, ALK-, BRAF- and KRAS-mutant NSCLC, treated with their corresponding TT. We identify a common path of drug adaptation, which invariably involves alveolar type 1 (AT1) differentiation and Rho-associated protein kinase (ROCK)-mediated cytoskeletal remodeling. We also isolate and characterize a rare population of early escapers, which represent the earliest resistance-initiating cells that emerge in the first hours of treatment from the AT1-like population. A phenotypic drug screen identify farnesyltransferase inhibitors (FTI) such as tipifarnib as the most effective drugs in preventing relapse to TT in vitro and in vivo in several models of oncogenic addiction, which is confirmed by genetic depletion of the farnesyltransferase. These findings pave the way for the development of treatments combining TT and FTI to effectively prevent tumor relapse in oncogene-addicted NSCLC patients.
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Dates et versions

hal-04727333 , version 1 (09-10-2024)

Identifiants

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Sarah Figarol, Célia Delahaye, Rémi Gence, Aurélia Doussine, Juan Pablo Cerapio, et al.. Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies. Nature Communications, 2024, 15 (1), pp.5345. ⟨10.1038/s41467-024-49360-4⟩. ⟨hal-04727333⟩
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