Our data highlight the potential of combined PI3K/mTOR/AKT and EGFR inhibition in KRAS-mutant CRC cells with relatively high levels of high-affinity EGFR ligands, with a need for further investigations on the therapeutic efficacy, mode of action, and tolerability for optimizing this combination in additional KRAS-mutant PDX models concurrently harboring other genetic alterations. Here, PIK3CA is linked to colorectal carcinoma.