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KRAS inhibitors: resistance drivers and combinatorial strategies

Tamara Isermann1, Christine Sers1, Channing J Der2

  • 1Charité - Universitätsmedizin Berlin, Institute of Pathology, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Trends in Cancer
|December 28, 2024
PubMed

Insights

Targeting KRAS mutations in cancer took 40 years. New KRAS G12C inhibitors show promise, but overcoming resistance and developing combination therapies are key challenges for effective cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • RAS genes, including KRAS, were identified as early cancer genes.
  • KRAS is a frequently mutated oncogene in various cancers.
  • Targeting KRAS mutations has been a long-standing challenge in cancer therapy.

Purpose of the Study:

  • To review the development of KRAS inhibitors.
  • To highlight mechanisms of resistance to KRAS-targeted therapies.
  • To discuss combination treatment strategies for RAS-mutant cancers.

Main Methods:

  • Literature review of KRAS research and drug development.
  • Analysis of resistance mechanisms in KRAS-mutant cancers.
  • Exploration of emerging combination therapy approaches.

Main Results:

  • The discovery of a druggable pocket in KRAS led to FDA-approved KRAS G12C inhibitors (sotorasib, adagrasib).
  • These approvals mark significant progress but also reveal challenges in overcoming resistance.
  • Resistance mechanisms and combination strategies are crucial for improving patient outcomes.

Conclusions:

  • Targeting KRAS mutations has advanced significantly with new inhibitors.
  • Addressing resistance mechanisms is essential for durable responses.
  • Combination therapies hold promise for enhancing the efficacy of KRAS-targeted treatments.
Keywords:
KRAScolorectal carcinomadrug resistancenon-small cell lung cancerpancreatic ductal adenocarcinoma

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