MEK blockade exhausts the transcriptional reserve of lipid modifications and sensitizes mutant HRAS to statins

Atorvastatin calcium (ATO) is a first-line lipid-lowering agent. While its antineoplastic activity has been reported in breast and pancreatic cancers, whether HRAS genotype dictates statin sensitivity in thyroid cancer has not been determined. Here, ATO preferentially killed HRAS-wild-type ( HRAS WT ) thyroid cancer cells by reducing AKT phosphorylation, but had little effect on HRAS - or PIK3CA -mutant thyroid cancer cells. Mechanistically, ATO blocked prenylation and membrane localization of wild-type HRAS, thereby inhibiting PI3K/AKT signaling essential for HRAS WT cells. Mutant HRAS instead activated MAPK/ERK, conferring intrinsic ATO resistance. Combining ATO with a MEK inhibitor synergistically suppressed HRAS-mutant cells by depleting the transcriptional reserve of lipid-modifying enzymes, co-inhibiting prenylation and palmitoylation and disrupting HRAS membrane anchorage. Taken together, this study demonstrates that ATO selectively eradicates HRAS WT thyroid cancer cells by suppressing the prenylation of HRAS, and proposes that MEK inhibition sensitizes HRAS -mutant thyroid cancers to ATO.