Disabling aggressive colorectal cancer by dual targeting of cancer cells and the microenvironment

Highlights• ERK1 protein was highly present in cancer-derived cell-free scaffolds from 5FU non-responding colorectal cancer patients, suggesting that ERK1-driven signaling imprinted in the cancer microenvironment may contribute to chemoresistance.• Ex vivo treatment with 5FU combined with a MEK1/2 inhibitor in patient-derived scaffolds repopulated with HT-29 cells produced stronger anti-tumor effects than either agent alone, significantly reducing cancer cell burden and suppressing stemness and EMT features - particularly in scaffolds with low intrinsic proliferative suppression, a recently identified marker of poor 5FU response in colorectal cancer.• In a murine model the combination treatment reduced metastatic spread and tumor burden versus 5FU alone, and the MEK1/2 inhibitor AZD8330 show acceptable safety and pharmacokinetics in Phase I studies, encouraging further development of a combination treatment strategy with 5FU in colorectal cancer.