In this study, we aimed to elucidate the potential benefit of targeting the PI3K signaling pathway, more specifically the PI3K p110α subunit, in CRC cells harboring mutations in KRAS and/or PIK3CA. For this purpose, human CRC cell lines were selected to closely mimic the mutational pattern found in CRC patients regarding hotspot mutations in KRAS and PIK3CA: HCT116 (KRASG13D, PIK3CAH1047R) and SW480 (KRASG12V). This evidence concerns the gene PIK3CA and colorectal carcinoma.