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REVIEW article

Front. Oncol.
Sec. Thoracic Oncology
Volume 14 - 2024 | doi: 10.3389/fonc.2024.1328728
This article is part of the Research Topic KRAS in Stage IV Non-Small Cell Lung Cancer View all 7 articles

Mechanisms of resistance to KRASG12C inhibitors in KRASG12Cmutated non-small cell lung cancer

Provisionally accepted
Ali Chour Ali Chour 1,2,3Anne-Claire Toffart Anne-Claire Toffart 4,5*Elodie Berton Elodie Berton 4Michael Duruisseaux Michael Duruisseaux 1,2,6
  • 1 Respiratory Department, Louis Pradel Hospital, Hospices Civils de Lyon Cancer Institute, Lyon, France
  • 2 Oncopharmacology Laboratory, Cancer Research Center of Lyon, UMR INSERM 1052 CNRS 5286, Lyon, France
  • 3 Université Claude Bernard Lyon 1, Lyon, Rhône-Alpes, France
  • 4 Service de Pneumologie et Physiologie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, Rhône-Alpes, France
  • 5 Institute for Advanced Biosciences, UGA/INSERM U1209/CNRS 5309, Université Grenoble Alpes, Grenobles, France
  • 6 Université Claude Bernard, Université de Lyon, Lyon, Rhône-Alpes, France

The final, formatted version of the article will be published soon.

    The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS(OFF)). The KRAS G12C mutation results in the accumulation of KRASG12C(OFF), promoting cell cycle survival and proliferation primarily through the canonical MAPK & PI3K pathways. The KRAS G12C mutation is found in 13% of lung adenocarcinomas. Previously considered undruggable, sotorasib and adagrasib are the first available OFF state KRASG12C inhibitors, but treatment resistance is frequent.In this review, after briefly summarizing the KRAS pathway and the mechanism of action of OFF state KRASG12C inhibitors, we discuss primary and acquired resistance mechanisms. Acquired resistance is the most frequent, with "on-target" mechanisms such as new KRAS mutation preventing inhibitors binding; and "off-target" mechanisms leading to bypass of KRAS through gain-of-function mutations in other oncogenes like NRAS, BRAF, RET; or loss-of-function mutations in tumor suppressor genes like PTEN. Other "off-target" mechanisms described include epithelial-to-mesenchymal transition and histological transformation. Multiple co-existing mechanisms can be found in patients, but few cases have been published.We highlight the lack of data on non-genomic resistance and the need for comprehensive clinical studies exploring histological, genomic, and non-genomic changes at resistance. This knowledge could help foster new treatment initiatives in this challenging context.

    Keywords: Non-small cell lung cancer, KRASG12C Mutation, KRASG12C inhibitors resistance, Translational research Non-Small Cell Lung Cancer, Translational research

    Received: 27 Oct 2023; Accepted: 25 Jul 2024.

    Copyright: © 2024 Chour, Toffart, Berton and Duruisseaux. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Anne-Claire Toffart, Service de Pneumologie et Physiologie, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, Rhône-Alpes, France

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.