KRAS: From undruggable to a druggable Cancer Target

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Updated: Dec 13, 2025

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Dipesh Uprety1, Alex A Adjei1

  • 1Department of Oncology, Mayo Clinic, Rochester, MN, USA.

Cancer Treatment Reviews
|July 26, 2020
PubMed

Insights

RAS mutations drive 30% of cancers. New targeted therapies show promise for inhibiting KRAS G12C, offering hope against this common cancer driver.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • RAS proteins, particularly KRAS, are frequently mutated in human cancers, acting as key oncogenes.
  • Mutated RAS is constitutively active, promoting uncontrolled cell proliferation and tumor growth.
  • Previous efforts to inhibit RAS directly have largely been unsuccessful.

Purpose of the Study:

  • To review the role of KRAS in tumorigenesis.
  • To summarize historical approaches to KRAS inhibition.
  • To discuss current and future strategies for targeting KRAS mutations.

Main Methods:

  • Review of existing literature on RAS mutations and targeted therapies.
  • Analysis of recent developments in small molecule inhibitors targeting KRAS G12C.
  • Exploration of complementary therapeutic strategies targeting downstream effectors.

Main Results:

  • Several novel small molecules specifically targeting KRAS G12C (e.g., AMG510, MRTX849) have been developed.
  • Inhibition of downstream pathways (SHP2, SOS1, eIF4) shows potential in KRAS-mutant cancers.
  • Renewed interest and progress in targeting KRAS-driven cancers.

Conclusions:

  • Targeting KRAS, especially the G12C mutation, is a rapidly advancing field with promising therapeutic options.
  • Combination strategies involving direct KRAS inhibition and pathway modulation may overcome resistance.
  • Future research holds significant potential for improving outcomes in KRAS-mutant cancers.
Keywords:
CancersDruggableG12CK-RASKrasUndruggable

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