Efficacious Combination Drug Treatment for Colorectal Cancer that Overcomes Resistance to KRAS G12C Inhibitors.

Recent advances in combinatorial chemistry led to the discovery of inhibitors targeting the KRAS G12C mutant protein. However, efficacy of its monotherapy on colorectal cancer (CRC) is limited. Thus, effective combination drugs should be explored for applicable CRC patients to fully benefit from the KRAS G12C inhibitor treatment. Here we employed a patient-derived CRC stem cell (PD-CRC-SC) spheroid culture and demonstrated that three-drug combination of inhibitors against KRAS G12C, EGFR, and FGFR synergistically suppressed the growth of CRC cells carrying the KRAS G12C mutation. Likewise, combination of KRAS G12C and SHP2 inhibitors was also effective. Importantly, activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in heregulin-responsive CRC cells canceled out the effect of KRAS G12C inhibition, which was largely overcome by PI3K inhibitors. These results reveal that evaluating efficacy of combination therapies with PD-CRC-SC spheroids can be a promising strategy to find the best regimen for individual CRC patients.