In this study, we investigated the efficacy of dual MEK‐PI3K inhibition in established KRAS mutated MUC2‐secreting colon cancer cells (LS174T), and patient‐derived in vitro and in vivo models (tumor explants and epithelial organoid [colonoid] cultures, and intraperitoneal [IP] murine xenografts) derived from KRAS mutated mucinous colon/appendix cancers. This evidence concerns the gene MUC2 and malignant colon neoplasm.