Altogether, we describe here a novel molecular circuitry, whereby soluble mediators released by microenvironmental elements (fibroblasts) modulate PTEN activity in CRC cells, causing paradoxical PI3K/mTORC1 activation and resulting in increased response to specific double PI3K/mTOR inhibitors in specific genetic contexts (KRAS-mut/PIK3CA-mut/PTEN-competent). Here, PIK3CD is linked to colorectal carcinoma.