Mevalonate pathway rewiring driven by enhancer remodelling confers resistance to KRAS inhibitors in colorectal cancer

KRAS inhibitors (KRASi) have emerged as promising new cancer therapeutics for KRAS-mutant cancers; however, resistance remains a potential clinical challenge. Here, we show that reactivation of ERK is a hallmark of KRASi-resistant colorectal cancers (CRCs) and further demonstrate that enhancer remodeling rewires cholesterol biosynthesis through the mevalonate (MVA) pathway to confer this resistance. Mechanistically, enhancer remodeling activates MVA pathway, which facilitates the trafficking of KRAS to the membrane and sustains the MAPK signaling despite KRAS inhibition. Pharmacological inhibition of the MVA pathway with statins effectively blocks KRAS localization to the cell membrane, overcoming KRASi resistance in CRC. Together, these findings identify epigenetic-metabolic coupling of cholesterol biosynthesis as a mechanism of KRASi resistance and highlight targetable metabolic vulnerability in KRAS-mutant CRC. Resistance to KRAS inhibitors (KRASi) remains clinically challenging. Here, the authors establish a panel of colorectal cancer organoids with differential resistance to pan-KRASi and show that it’s driven by enhancer remodelling rewiring cholesterol biosynthesis through the mevalonate pathway.