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

Author

Listed:
  • 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
    service de pneumologie)

  • Clara Morin

    (Université de Toulouse, Université Toulouse III Paul Sabatier
    service de pneumologie)

  • 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
    Laboratoire de Biologie Médicale Oncologique)

  • Anne Casanova

    (Laboratoire de Biologie Médicale Oncologique)

  • Anne Pradines

    (Université de Toulouse, Université Toulouse III Paul Sabatier
    Laboratoire de Biologie Médicale Oncologique)

  • Julien Mazieres

    (Université de Toulouse, Université Toulouse III Paul Sabatier
    service de pneumologie)

  • Gilles Favre

    (Université de Toulouse, Université Toulouse III Paul Sabatier
    Laboratoire de Biologie Médicale Oncologique)

  • Olivier Calvayrac

    (Université de Toulouse, Université Toulouse III Paul Sabatier)

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.

Suggested Citation

  • Sarah Figarol & Célia Delahaye & Rémi Gence & Aurélia Doussine & Juan Pablo Cerapio & Mathylda Brachais & Claudine Tardy & Nicolas Béry & Raghda Asslan & Jacques Colinge & Jean-Philippe Villemin & Ant, 2024. "Farnesyltransferase inhibition overcomes oncogene-addicted non-small cell lung cancer adaptive resistance to targeted therapies," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49360-4
    DOI: 10.1038/s41467-024-49360-4
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