Mechanistically, we show that the elevated PI3K/AKT/p65 signaling axis in rCAFs prohibits chemotherapy-induced cell death and increases TGFα secretion, which, in turn, promotes cancer cell chemoresistance by activating the EGFR/Src/STAT3 mediated cell survival pathway and repressing the p53/caspase-3 dependent apoptosis. The gene discussed is CASP3; the disease is cancer.