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Updated: Dec 2, 2025

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Therapeutics Targeting Mutant KRAS

Kyaw Z Thein1, Amadeo B Biter2, David S Hong2

  • 1Division of Hematology and Medical Oncology, Oregon Health and Science University/Knight Cancer Institute, Portland, Oregon 97239, USA;

Annual Review of Medicine
|November 3, 2020
PubMed

Insights

Genetic aberrations in rat sarcoma (RAS) viral oncogene, particularly KRAS mutations, drive cancer. New covalent inhibitors targeting KRASG12C show promise, but combination strategies are vital for overcoming resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Rat sarcoma (RAS) viral oncogene aberrations are prevalent in human cancers.
  • RAS signaling pathways, including MAPK and PI3K, are critical for tumorigenesis.
  • KRAS is the most frequently mutated RAS isoform, with codon 12 mutations common in malignancies.

Purpose of the Study:

  • To review the role of RAS mutations in cancer.
  • To discuss novel therapeutic strategies targeting KRAS, especially KRASG12C.
  • To highlight the importance of combination therapies for KRAS-mutant tumors.

Main Methods:

  • Review of existing literature on RAS oncogenes and targeted therapies.
  • Analysis of recent developments in covalent allosteric inhibitors.
  • Discussion of resistance mechanisms and combination strategies.

Main Results:

  • KRAS mutations, particularly at codon 12, are key drivers of many cancers.
  • Covalent allosteric inhibitors (e.g., AMG 510, MRTX849) targeting KRASG12C demonstrate early therapeutic potential.
  • Resistance to KRAS-targeted therapies necessitates combination approaches.

Conclusions:

  • Targeting KRAS mutations represents a significant area of cancer research.
  • Novel covalent inhibitors offer a promising avenue for treating KRAS-mutant cancers.
  • Overcoming therapeutic resistance through combination strategies is crucial for effective cancer treatment.
Keywords:
AMG 510KRAS mutationsKRASG12C inhibitorsMRTX849RASrat sarcoma viral oncogenesynthetic lethality

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