We present a comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using the FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (a ribosomal protein S6 kinase inhibitor) in CRC cell lines and mouse- and patient-derived organoids. Here, AKT1 is linked to colorectal carcinoma.