2. Academic Validation
  3. ELOVL6 activity attenuation induces mutant KRAS degradation

ELOVL6 activity attenuation induces mutant KRAS degradation

  • Nat Chem Biol. 2025 Sep 15. doi: 10.1038/s41589-025-01998-x.
Xiyue Hu 1,  Ranjit Singh Atwal 1 2,  Sophie Xiao 1,  Sharif U Ahmed 1 3,  Zongjie Wang 1 2 3,  Chenlin Zhao 1,  Hansen Wang 4,  Shana O Kelley 5 6 7 8 9
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2 Chan Zuckerberg Biohub Chicago, Chicago, IL, USA.
  • 3 Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
  • 4 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
  • 5 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. shana.kelley@northwestern.edu.
  • 6 Chan Zuckerberg Biohub Chicago, Chicago, IL, USA. shana.kelley@northwestern.edu.
  • 7 Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA. shana.kelley@northwestern.edu.
  • 8 Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. shana.kelley@northwestern.edu.
  • 9 Department of Chemistry, Northwestern University, Evanston, IL, USA. shana.kelley@northwestern.edu.
PMID: 40954224 DOI: 10.1038/s41589-025-01998-x
Abstract

KRAS is one of the most frequently mutated oncogenes in Cancer. Targeting mutant KRAS directly has been challenging because of minor structural changes caused by mutations. Despite recent success in targeting KRAS-G12C, targeted therapy for another hotspot mutant, KRAS-G12V, has not been described. We used CRISPR-Cas9 genome-wide knockout screens to identify genes that specifically modulate mutant KRAS harboring the G12V substitution. Our top hit, a fatty acid elongase (ELOVL6), showed remarkable selectivity in diminishing KRAS-G12V protein expression and aberrant oncogenic signaling associated with mutant KRAS. Our studies reveal that ELOVL6 can be targeted to control the production of Phospholipids exploited by KRAS mutants for function-targeted and trigger-targeted degradation of the protein. Our results demonstrate the basis for a first-in-class small-molecule inhibitor to selectively clear KRAS-G12V from Cancer cells.

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