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

Sarah Figarol, Célia Delahaye, Rémi Gence, Aurélia Doussine, Juan Pablo Cerapio, Mathylda Brachais, Claudine Tardy, Nicolas Béry, Raghda Asslan, Jacques Colinge, Jean-Philippe Villemin, Antonio Maraver, Irene Ferrer, Luis Paz-Ares, Linda Kessler, Francis Burrows, Isabelle Lajoie-Mazenc, Vincent Dongay, Clara Morin, Amélie Florent, Sandra Pagano, Estelle Taranchon-Clermont, Anne Casanova, Anne Pradines, Julien Mazieres, Gilles Favre () and Olivier Calvayrac ()
Additional contact information
Sarah Figarol: Université de Toulouse, Université Toulouse III Paul Sabatier
Célia Delahaye: Université de Toulouse, Université Toulouse III Paul Sabatier
Rémi Gence: Université de Toulouse, Université Toulouse III Paul Sabatier
Aurélia Doussine: Université de Toulouse, Université Toulouse III Paul Sabatier
Juan Pablo Cerapio: Université de Toulouse, Université Toulouse III Paul Sabatier
Mathylda Brachais: Université de Toulouse, Université Toulouse III Paul Sabatier
Claudine Tardy: Université de Toulouse, Université Toulouse III Paul Sabatier
Nicolas Béry: Université de Toulouse, Université Toulouse III Paul Sabatier
Raghda Asslan: Université de Toulouse, Université Toulouse III Paul Sabatier
Jacques Colinge: Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM)
Jean-Philippe Villemin: Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM)
Antonio Maraver: Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM)
Irene Ferrer: Instituto de Investigación Hospital 12 de Octubre-CNIO
Luis Paz-Ares: Instituto de Investigación Hospital 12 de Octubre-CNIO
Linda Kessler: Inc
Francis Burrows: Inc
Isabelle Lajoie-Mazenc: Université de Toulouse, Université Toulouse III Paul Sabatier
Vincent Dongay: Université de Toulouse, Université Toulouse III Paul Sabatier
Clara Morin: Université de Toulouse, Université Toulouse III Paul Sabatier
Amélie Florent: Université de Toulouse, Université Toulouse III Paul Sabatier
Sandra Pagano: Université de Toulouse, Université Toulouse III Paul Sabatier
Estelle Taranchon-Clermont: Université de Toulouse, Université Toulouse III Paul Sabatier
Anne Casanova: Laboratoire de Biologie Médicale Oncologique
Anne Pradines: Université de Toulouse, Université Toulouse III Paul Sabatier
Julien Mazieres: Université de Toulouse, Université Toulouse III Paul Sabatier
Gilles Favre: Université de Toulouse, Université Toulouse III Paul Sabatier
Olivier Calvayrac: Université de Toulouse, Université Toulouse III Paul Sabatier

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49360-4

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