Related Experiment Video

Updated: Nov 10, 2025

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Mechanisms of Resistance to KRASG12C-Targeted Therapy

Neal S Akhave1, Amadeo B Biter2, David S Hong3

  • 1Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Cancer Discovery
|April 6, 2021
PubMed

Insights

KRAS inhibitors offer new cancer treatment options but resistance develops quickly. Research is exploring combination strategies to overcome resistance mechanisms and improve long-term patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • KRAS mutations are common drivers of cancer with poor prognosis.
  • KRAS inhibitors targeting KRAS G12C mutations show initial clinical responses.
  • Tumor resistance limits the long-term effectiveness of KRAS-targeted therapies.

Purpose of the Study:

  • To review and understand the mechanisms of resistance to KRAS inhibitors.
  • To identify strategies for overcoming resistance to achieve durable clinical responses.

Main Methods:

  • Review of preclinical studies on KRAS inhibitor resistance.
  • Analysis of proposed resistance mechanisms including MAPK reactivation, cell-cycle transition, and immune defects.

Main Results:

  • KRAS inhibitors, while effective, lead to acquired resistance.
  • Mechanisms of resistance involve MAPK pathway reactivation, CDK4/6-driven cell-cycle progression, and immune system alterations.

Conclusions:

  • Understanding resistance mechanisms is crucial for developing effective combination therapies.
  • Strategies to overcome resistance are essential for achieving long-term disease control in KRAS-mutated cancers.

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