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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
Summary
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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