| Added by | jacques.colinge |
|---|---|
| Group name | EquipeJC |
| Item Type | Journal Article |
| Title | Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies |
| Creator | Figarol et al. |
| Author | Sarah Figarol |
| Author | Célia Delahaye |
| Author | Rémi Gence |
| Author | Aurélia Doussine |
| Author | Juan Pablo Cerapio |
| Author | Mathylda Brachais |
| Author | Claudine Tardy |
| Author | Nicolas Béry |
| Author | Raghda Asslan |
| Author | Jacques Colinge |
| Author | Jean-Philippe Villemin |
| Author | Antonio Maraver |
| Author | Irene Ferrer |
| Author | Luis Paz-Ares |
| Author | Linda Kessler |
| Author | Francis Burrows |
| Author | Isabelle Lajoie-Mazenc |
| Author | Vincent Dongay |
| Author | Clara Morin |
| Author | Amélie Florent |
| Author | Sandra Pagano |
| Author | Estelle Taranchon-Clermont |
| Author | Anne Casanova |
| Author | Anne Pradines |
| Author | Gilles Favre |
| Author | Olivier Calvayrac |
| 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. |
| Publication | Nature Communications |
| Volume | 15 |
| Issue | 1 |
| Pages | 5345 |
| Date | 2024-06-27 |
| Journal Abbr | Nat Commun |
| Language | eng |
| DOI | 10.1038/s41467-024-49360-4 |
| ISSN | 2041-1723 |
| Library Catalog | PubMed |
| Extra | PMID: 38937474 PMCID: PMC11211478 |
| Tags | Animals, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Resistance, Neoplasm, Enzyme Inhibitors, Farnesyltranstransferase, Female, Humans, Lung Neoplasms, Mice, Molecular Targeted Therapy, Oncogene Addiction, Oncogenes, original, postdoc, Quinolones, Xenograft Model Antitumor Assays |
| Date Added | 2024/09/08 - 16:55:42 |
| Date Modified | 2024/09/08 - 17:01:22 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
