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Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers

Andrew J Aguirre1,2,3, William C Hahn1,2,3

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215.

Cold Spring Harbor Perspectives in Medicine
|November 5, 2017
PubMed

Insights

Targeting KRAS mutations, common in cancer, is difficult. This review explores synthetic lethal vulnerabilities in KRAS-mutant cancers, offering potential new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS is the most frequently mutated oncogene in human cancers.
  • KRAS-mutant cancers rely on sustained KRAS signaling, making it a key therapeutic target.
  • Direct KRAS inhibition has proven challenging.

Purpose of the Study:

  • To review identified codependencies and synthetic lethal interactions in KRAS-mutant cancers.
  • To highlight potential therapeutic opportunities arising from these vulnerabilities.

Main Methods:

  • Review of existing literature on KRAS-mutant cancer vulnerabilities.
  • Analysis of results from functional genetic screens for KRAS synthetic lethal targets.

Main Results:

  • KRAS activates multiple effector pathways promoting cancer cell proliferation and survival.
  • KRAS-mutant cancer cells exhibit unique vulnerabilities due to oncogenic stress and compensatory mechanisms.
  • Numerous synthetic lethal interactions with KRAS have been identified.

Conclusions:

  • Targeting synthetic lethal partners represents a promising alternative therapeutic strategy for KRAS-mutant cancers.
  • Identified vulnerabilities offer tractable therapeutic opportunities for treating KRAS-driven malignancies.

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