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ELOVL6 activity attenuation induces mutant KRAS degradation

Xiyue Hu1, Ranjit Singh Atwal1,2, Sophie Xiao1

  • 1Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Nature Chemical Biology
|September 15, 2025
PubMed

Insights

Researchers identified fatty acid elongase 6 (ELOVL6) as a key target to reduce KRAS-G12V oncoprotein in cancer. This discovery paves the way for new KRAS-G12V-specific cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS mutations are common in cancer, but targeting them is difficult due to subtle structural changes.
  • While KRAS-G12C is targeted, effective therapies for KRAS-G12V remain elusive.
  • Identifying specific vulnerabilities of KRAS-G12V is crucial for developing new cancer treatments.

Purpose of the Study:

  • To identify genes that specifically modulate the KRAS-G12V mutant.
  • To explore ELOVL6 as a potential therapeutic target for KRAS-G12V-driven cancers.
  • To understand the mechanism by which ELOVL6 affects KRAS-G12V.

Main Methods:

  • CRISPR-Cas9 genome-wide knockout screens were employed to identify modulators of KRAS-G12V.
  • Protein expression levels and oncogenic signaling pathways were analyzed.
  • Phospholipid production pathways were investigated in relation to KRAS-G12V function.

Main Results:

  • ELOVL6 was identified as a top hit, selectively reducing KRAS-G12V protein expression.
  • Targeting ELOVL6 diminished aberrant oncogenic signaling driven by KRAS-G12V.
  • ELOVL6 was found to regulate phospholipid production essential for KRAS-G12V function.

Conclusions:

  • ELOVL6 is a promising therapeutic target for KRAS-G12V-mutated cancers.
  • Targeting ELOVL6 can lead to the degradation of KRAS-G12V oncoprotein.
  • This research provides a foundation for developing novel small-molecule inhibitors against KRAS-G12V.

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