"What we decided is that rather than trying to get a small molecule to attack those amino acids specifically, let's try to find a gene or a protein that actually regulates the levels of that mutated protein,"
"When we hit this lipid elongase, it selectively took out the lipid that the mutated KRAS liked, and so then the mutated form of the protein fall"
KRAS mutations are common in pancreatic, colon, and non-small cell lung cancers and present major targeting challenges due to mutation-induced structural changes. KRAS-G12V represents a difficult-to-target oncogenic variant that may be modulated indirectly. Genome-wide CRISPR-Cas9 knockout screening in wild-type and KRAS-G12V cell lines identified ELOVL6 as a regulator whose activity influences KRAS-G12V protein abundance. ELOVL6 functions as a fatty acid elongase that produces plasma membrane lipids required for KRAS-G12V anchoring. Disruption of ELOVL6 diminishes the lipid environment favored by KRAS-G12V, selectively reducing its membrane association and protein levels and indicating a therapeutic avenue.
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