We here performed an unbiased drug screen for signaling pathways documented to be contributors to CRC (61–65), with an aim to identify novel drug combinations with EGFR-small-molecule inhibitors that could offer a therapeutic advantage against KRAS-driven cancers and overcome acquired radioresistance and cetuximab resistance mediated by stem-like (WNT activated) and KRAS mutation phenotype utilizing tumoroid models of COAD. This evidence concerns the gene EGFR and colorectal carcinoma.