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Updated: Aug 11, 2025

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

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Multiple initiatives to conquer KRAS G12C inhibitor resistance from the perspective of clinical therapy

Junmin Zhang1,2, Juanhong Zhang1,2,3, Elaine Lai-Han Leung4

  • 1State Key Laboratory of Quality Research in Chinese Medicine, and Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, Macau University of Science and Technology, Macau, China.

Expert Opinion on Investigational Drugs
|February 7, 2023
PubMed
Abstract

Insights

Targeted covalent inhibitors for KRAS G12C cancers show promise, but resistance is a challenge. Strategies to overcome this resistance are crucial for improving patient outcomes and achieving long-term disease control.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • KRAS G12C mutations are key drivers in various cancers.
  • Targeted covalent inhibitors offer a novel therapeutic approach for KRAS G12C-driven cancers.
  • Clinical resistance to KRAS G12C inhibitors has emerged as a significant challenge.

Purpose of the Study:

  • To review and emphasize strategies for overcoming KRAS G12C inhibitor resistance in clinical cancer therapy.
  • To provide expert perspectives on future research and development directions.
  • To highlight the importance of understanding resistance mechanisms for improved therapeutic effects.

Main Methods:

  • Review of preclinical and clinical data on KRAS G12C inhibitor resistance.
  • Analysis of emerging resistance mechanisms.
  • Discussion of rational combination dosing strategies.

Main Results:

  • Resistance to KRAS G12C inhibitors is a documented clinical issue.
  • Understanding resistance mechanisms is vital for therapeutic advancement.
  • Combination therapies and further research are needed to enhance efficacy.

Conclusions:

  • Overcoming KRAS G12C inhibitor resistance requires a multi-faceted approach.
  • Continued exploration of resistance mechanisms and rational combination therapies are essential for long-term disease control.
  • Future research should focus on developing next-generation inhibitors and combination strategies.
Keywords:
AMG 510KRAS G12CMRTX 849drug resistancetargeted therapy

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