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Updated: Nov 20, 2025

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

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Mechanisms of Resistance to KRASG12C Inhibitors

Victoria Dunnett-Kane1,2, Pantelis Nicola2,3, Fiona Blackhall2,3,4

  • 1Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester M23 9LT, UK.

Cancers
|January 20, 2021
PubMed

Insights

Targeting KRAS G12C oncogenes with new drugs shows promise, but resistance is a challenge. This review explores resistance mechanisms and combination therapies to overcome limitations for KRAS G12C inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • KRAS is a common human oncogene, historically considered
  • undruggable
  • due to difficulties in developing direct inhibitors.
  • Recent advancements have led to subtype-specific inhibitors, particularly for KRAS G12C mutations.
  • Drugs like adagrasib and sotorasib targeting KRAS G12C have entered clinical trials with early efficacy signals.

Purpose of the Study:

  • To review the current evidence for KRAS G12C inhibitors.
  • To discuss identified mechanisms of drug resistance to KRAS G12C inhibitors.
  • To explore potential strategies and combination therapies to overcome resistance.

Main Methods:

  • Literature review of preclinical studies and clinical trials.
  • Analysis of resistance mechanisms reported in scientific literature.
  • Identification and discussion of potential combination therapy targets.

Main Results:

  • KRAS G12C inhibitors demonstrate early clinical efficacy.
  • Drug resistance is a significant anticipated limitation for KRAS G12C inhibitors in vivo.
  • Several resistance mechanisms have been identified in preclinical studies.

Conclusions:

  • KRAS G12C inhibitors represent a significant advancement in targeting oncogenic KRAS.
  • Overcoming drug resistance through combination therapies is crucial for sustained clinical benefit.
  • Ongoing clinical trials are investigating combination strategies including SHP2, RTKs, downstream effectors, and PD1/PDL1 inhibitors.
Keywords:
G12CKRASNSCLCdrug resistanceoncogenetargeted therapy

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