Targeting c-MET to Enhance the Efficacy of Olaparib in Prostate Cancer

Zhenwei Wang,1,2 Zhihong Dai,1,* Bingwei Wang,2 Yuren Gao,1 Xiang Gao,1 Liang Wang,1 Sihai Zhou,1 Liqin Yang,1 Xiaofu Qiu,2,3,* Zhiyu Liu1 1Department of Urinary Surgery, Second Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 2Department of Urology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, People’s Republic of China; 3The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhiyu Liu Tel +86 15541190788Email lzydoct@163.comPurpose: Prostate cancer is the second leading cause of cancer death in men worldwide. Olaparib is clinically approved for the treatment prostate cancer, but cytotoxicity and off-target effects including DNA damage limit its clinical applications. In the current study, new strategies to improve the therapeutic efficacy of olaparib for the treatment of prostate cancer were investigated.Methods: Two prostate cancer cell lines were exposed to the c-MET inhibitor PHA665752 and/or the PARP inhibitor olaparib. Cell counting kit-8, colony formation assays, and transwell assays were conducted to evaluate the cytotoxicity of olaparib alone or in combination with PHA665752 in prostate cancer cell lines. Western blotting, immunofluorescence staining, and the comet assay were used to assess the effects of PHA665752 on olaparib-induced DNA damage.Results: Combined inhibition of c-MET and PARP resulted in effective and synergistic blocking of the growth of prostate cancer cell lines. Invasion and migration were significantly suppressed when the agents were combined. Mechanistically, dual blocking of PARP and c-MET in prostate cancer cell lines was associated with an impaired DNA damage response. Interestingly, immunofluorescence staining analysis of RAD51 protein indicated that the c-MET inhibitor PHA665752 significantly impaired homologous repair via downregulated translocation of RAD51 into the nucleus in prostate cancer cells.Conclusion: The combination of the c-MET inhibitor PHA665752 and the PARP inhibitor olaparib may be a promising therapeutic strategy in patients with prostate cancer.Keywords: combination therapy, PARP inhibitor, PHA665752, prostate cancer