Enhancer Remodeling-Driven Mevalonate Pathway Confers Resistance to KRAS Inhibitor in Colorectal Cancer

This study investigates the resistance mechanisms to pan-KRAS inhibitors in colorectal cancer (CRC). We established a panel of patient-derived organoids (PDOs) and cell lines with differential sensitivity to pan-KRAS inhibitors. Integrated epigenomic (ChIP-seq for H3K27ac and H3K4me3) and transcriptomic (RNA-seq) profiling revealed that enhancer remodeling drives compensatory activation of the mevalonate (MVA) pathway in resistant models. The MVA pathway upregulation facilitates KRAS membrane trafficking via protein farnesylation, thereby sustaining ERK activation and conferring resistance to KRAS inhibitors. Pharmacological inhibition of the MVA pathway using statins restores therapeutic sensitivity and enhances efficacy of KRAS inhibitors in cellular, PDO, and PDX models.