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Resistance to KRASG12C Inhibitors in Non-Small Cell Lung Cancer

Juan Bautista Blaquier1, Andrés Felipe Cardona2,3,4, Gonzalo Recondo1

  • 1Thoracic Oncology Unit, Medical Oncology, Center for Medical Education and Clinical Research (CEMIC), Buenos Aires, Argentina.

Frontiers in Oncology
|January 10, 2022
PubMed

Insights

KRAS G12C inhibitors show promise in lung cancer but resistance is common. Understanding intrinsic and acquired resistance mechanisms is key to developing effective strategies against KRAS-mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • KRAS mutations are common drivers of cancer.
  • KRAS G12C inhibitors (sotorasib, adagrasib) target this mutation, showing early clinical promise in non-small cell lung cancer.
  • Resistance to these targeted therapies is an emerging clinical challenge.

Purpose of the Study:

  • To review the molecular mechanisms of intrinsic and acquired resistance to KRAS G12C inhibitors.
  • To discuss potential clinical strategies for overcoming resistance in KRAS G12C-mutant non-small cell lung cancer.

Main Methods:

  • Literature review of pre-clinical models and patient data.
  • Analysis of molecular mechanisms underlying resistance.
  • Discussion of clinical trial outcomes and therapeutic strategies.

Main Results:

  • Intrinsic resistance can involve reactivation of signaling pathways like ERK via receptor tyrosine kinases.
  • Acquired resistance mechanisms include new KRAS mutations (e.g., Y96D/C) and alterations in RAS-MAPK pathway effectors.
  • Resistance is a significant factor limiting the long-term efficacy of KRAS G12C inhibitors.

Conclusions:

  • KRAS G12C inhibitors represent a significant advance, but resistance necessitates further research.
  • Identifying and targeting resistance mechanisms is crucial for improving patient outcomes in KRAS-mutant lung cancer.
  • Combination therapies and novel therapeutic approaches are needed to overcome resistance.
Keywords:
KRASG12CNSCLCY96Dresistance mechanismstarget therapy

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