DNA double-strand breaks (DSBs) caused by
platinum drugs are dangerous lesions that kill
cancer cells in
chemotherapy. Repair of
DSB by homologous recombination (HR) and nonhomologous end joining (NHEJ) is frequently associated with
platinum resistance in
ovarian cancer. While the role of the HR pathway and HR-targeting strategy in
platinum resistance is well studied, dissecting and targeting NHEJ machinery to overcome
platinum resistance in
ovarian cancer remain largely unexplored. Here, through an NHEJ pathway-focused gene RNAi screen, we found that the knockdown of XRCC4 significantly sensitized
cisplatin treatment in the
platinum-resistant
ovarian cancer cell lines. Moreover, upregulation of XRCC4 is observed in a panel of
platinum-resistant cell lines relative to the parental cell lines, as well as in
ovarian cancer patients with poor progression-free survival. Mechanistically, the increased sensitivity to
cisplatin upon XRCC4 knockdown was caused by accumulated DNA damage. In
cisplatin-resistant
ovarian cancer, the JNK-cJUN complex, activated by
cisplatin, translocated into the nucleus and promoted the transcription of XRCC4 to confer
cisplatin resistance. Knockdown of XRCC4 or treatment of the JNK inhibitor led to the attenuation of
cisplatin-resistant
tumor growth in the xenograft mouse models. These data suggest targeting XRCC4 is a potential strategy for ovarian
cisplatin resistance in
ovarian cancer.