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

Carcinoma, Non-Small-Cell Lung / genetics Humans Farnesyltranstransferase / antagonists & inhibitors Lung Neoplasms / genetics Drug Resistance, Neoplasm / genetics Cell Line, Tumor Animals Mice Oncogene Addiction / genetics Molecular Targeted Therapy Enzyme Inhibitors / pharmacology Female Xenograft Model Antitumor Assays Oncogenes / genetics Antineoplastic Agents / pharmacology Quinolones

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
27 Jun 2024
Historique:
received: 02 03 2024
accepted: 03 06 2024
medline: 28 6 2024
pubmed: 28 6 2024
entrez: 27 6 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-49360-4 PMID: 38937474
pubmed: 38937474
doi: 10.1038/s41467-024-49360-4
pii: 10.1038/s41467-024-49360-4
doi:

Substances chimiques

Farnesyltranstransferase EC 2.5.1.29
tipifarnib MAT637500A
Enzyme Inhibitors 0
Antineoplastic Agents 0
Quinolones 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

5345

Subventions

Organisme : Fondation ARC pour la Recherche sur le Cancer (ARC Foundation for Cancer Research)
ID : PJA2
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : DEQ20170839117
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : DEQ20170839117
Organisme : Fondation pour la Recherche Médicale (Foundation for Medical Research in France)
ID : DEQ20170839117
Organisme : Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research)
ID : Inserm
Organisme : Institut National de la Santé et de la Recherche Médicale (National Institute of Health and Medical Research)
ID : Inserm
Organisme : Institut National Du Cancer (French National Cancer Institute)
ID : PRT-K18-048
Organisme : Ligue Contre le Cancer
ID : LNCC

Informations de copyright

© 2024. The Author(s).

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Auteurs

Sarah Figarol (S)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
ORCID: 0000-0002-3863-563X

Célia Delahaye (C)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
ORCID: 0009-0004-7966-5597

Rémi Gence (R)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.

Aurélia Doussine (A)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.

Juan Pablo Cerapio (JP)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
ORCID: 0000-0002-3032-3180

Mathylda Brachais (M)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.

Claudine Tardy (C)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.

Nicolas Béry (N)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
ORCID: 0000-0002-2643-3897

Raghda Asslan (R)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.

Jacques Colinge (J)

Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France.
ORCID: 0000-0003-2466-4824

Jean-Philippe Villemin (JP)

Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France.

Antonio Maraver (A)

Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France.
ORCID: 0000-0002-5527-5680

Irene Ferrer (I)

Unidad de Investigación Clínica de Cáncer de Pulmón, Instituto de Investigación Hospital 12 de Octubre-CNIO, Madrid, Spain.
ORCID: 0000-0002-2748-2607

Luis Paz-Ares (L)

Unidad de Investigación Clínica de Cáncer de Pulmón, Instituto de Investigación Hospital 12 de Octubre-CNIO, Madrid, Spain.

Linda Kessler (L)

Kura Oncology, Inc, Calif, USA.

Francis Burrows (F)

Kura Oncology, Inc, Calif, USA.

Isabelle Lajoie-Mazenc (I)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.

Vincent Dongay (V)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
Centre Hospitalier Universitaire (CHU) de Toulouse, service de pneumologie, Toulouse, France.

Clara Morin (C)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
Centre Hospitalier Universitaire (CHU) de Toulouse, service de pneumologie, Toulouse, France.

Amélie Florent (A)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.

Sandra Pagano (S)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
ORCID: 0000-0003-1758-3233

Estelle Taranchon-Clermont (E)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
Oncopole Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratoire de Biologie Médicale Oncologique, Toulouse, France.

Anne Casanova (A)

Oncopole Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratoire de Biologie Médicale Oncologique, Toulouse, France.

Anne Pradines (A)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
Oncopole Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratoire de Biologie Médicale Oncologique, Toulouse, France.

Julien Mazieres (J)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France.
Centre Hospitalier Universitaire (CHU) de Toulouse, service de pneumologie, Toulouse, France.
ORCID: 0000-0002-5921-7613

Gilles Favre (G)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France. favre.gilles@iuct-oncopole.fr.
Oncopole Claudius Regaud, Institut Universitaire du Cancer de Toulouse-Oncopole, Laboratoire de Biologie Médicale Oncologique, Toulouse, France. favre.gilles@iuct-oncopole.fr.
ORCID: 0000-0002-2344-1883

Olivier Calvayrac (O)

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, CNRS, Université de Toulouse, Université Toulouse III Paul Sabatier, Toulouse, France. olivier.calvayrac@inserm.fr.
ORCID: 0000-0002-0908-8323

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Classifications MeSH

questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Tumeurs des bronches › Carcinome bronchogénique › Carcinome pulmonaire non à petites cellules › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Alkyl et aryl transferases › Farnesyltranstransferase › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Eucaryotes › Animaux › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Dépendance oncogène › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Thérapie moléculaire ciblée › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Gènes tumoraux › Oncogènes › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Farnesyltransferase inhibition overcomes...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Quinoléines › Quinolinone › Farnesyltransferase inhibition overcomes...