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. Overall design: This study includes RNA-seq and ChIP-seq analyses of KRAS inhibitor-sensitive and resistant models. For RNA-seq: 1) LS174T parental vs resistant cells; 2) DLD1 cells treated with BI-2865 for 24h; 3) PDO cohorts with differential sensitivity to BI-2865. For ChIP-seq: H3K27ac and H3K4me3 profiling in LS174T parental vs resistant cells. Biological replicates were included for all experiments.