Similar to that functional situation, which requires double MEK/ERK blockade to shut the pathway down and support clinical activity (20–22), here we show that fibroblast-CM induced paradoxical PI3K/mTORC1 specifically sensitizes PTEN-competent CRC cells to double PI3K/mTOR, but not to single PI3K, AKT, or mTOR, inhibition. This evidence concerns the gene PIK3CA and colorectal carcinoma.