AKT1 and neoplasm: PGE2 stimulates the PIK3CA/AKT pathway primarily through EP4 receptor activation, which in turn either directly activates PIK3CA enzyme or EGFR transactivation through an intermediate β-arrestin-1–SRC complex or by stimulating secretion of EGF-like ligands.19,26,27 Aspirin inhibits PIK3CA/AKT pathway by reducing PGE2 levels and has a greater inhibitory effect on tumor growth in CRC cells with activating PIK3CA mutations.28,29