Regarding the critical role of apoptosis-resistance and EMT in acquired resistance to radiotherapy, chemotherapy, and targeted therapy, our result that APE1-endonuclease activity can interfere with miR-221/222 biogenesis represents, to the best of our knowledge, a novel combinational therapeutic approach via using APE1 inhibitors to enhance efficacy of current cancer treatment. The gene discussed is APEX1; the disease is cancer.