Mutant KRAS/BRAF Reprograms the Enhancer Landscape via GATA1 to Drive Chemoresistance

Despite advances in the detection and management of colorectal cancers, resistance to anti-cancer therapies remains a significant challenge. Activating mutations in KRAS and BRAF are frequently observed in colorectal cancers and have been associated with aggressive tumors and poor survival after chemotherapy. In the present study, we demonstrate that mutations in KRAS/BRAF alter the enhancer landscape of tumor cells, which leads to the resistance of the cornerstone colorectal cancer chemotherapeutic agent 5-fluorouracil (5-FU) through activation of transcription factor GATA1. Targeted inhibition of GATA1 reverses epigenetic changes in KRAS mutant cells and restores sensitivity to 5-FU. These results indicate a novel therapeutic opportunity for tailoring individualized therapy in human colorectal cancer. RNA-seq and H3K4me1- H3K27ac-ChIP-seq were performed on GATA1 KO HCT116 cells. RNA-seq was performed on K7174-treated HCT116 cells and Colo320 cells expressing vector, wildtype and G12V KRAS.