We showed an amplifying regulatory loop involving the direct interaction of miR-203 with the 3'UTR of EGFR ligands, AREG, EREG, and TGFA. In addition, we determined the mechanisms by which miR-203 overexpression contributes to TKIs-resistant Ras-activated prostate cancer cell apoptosis by targeting the 3'UTR of anti-apoptotic proteins, API5, BIRC2, and TRIAP1. Using a RAS mutation model, our study provides a novel functional link between miR-203 loss and increased EGFR ligands and shows how miR-203 regulates EGFR signaling response genes in prostate cancer metastasis and TKIs resistance. This evidence concerns the gene EREG and Familial prostate cancer.