Gemcitabine is one of the current first-line chemotherapy agents in pancreatic cancer treatment. However, the response rate of pancreatic cancer patients to gemcitabine treatment is lower than 20%. Among the potential targeted therapies for pancreatic cancer patients, PARP inhibitor (Olaparib) has been approved by the U.S. Food and Drug Administration for maintenance treatment of metastatic pancreatic adenocarcinoma patients with germline BRCA-mutation. Taking advantages of the high oxidative stress in most pancreatic cancer cells, therapeutic agents that enhance the burden of oxidative DNA damages in these cancer cells can be introduced in novel treatment strategies. Because c-MET overexpression positively correlates with poor prognosis in pancreatic cancer, and our previous studies show that oxidative stress induced-nuclear c-MET phosphorylates PARP1 to reduce oxidative DNA damages, we focused on developing novel treatment strategies by combining c-MET inhibitors (crizotinib and tivantinib) with either gemcitabine or olaparib. In this study, we found that gemcitabine induced nuclear accumulation of c-MET, and that tivantinib reduced c-MET mediated PARP1 phosphorylation in both BxPC-3 and L3.6pl pancreatic cancer cell lines. We also found that combination of tivantinib with either gemcitabine or Olaparib induced more DNA damages than the single agent treatments. Further, we demonstrated the synergistic effects of c-MET inhibitors combined with gemcitabine or Olaparib in pancreatic cancer cell lines, suggesting that combining c-MET inhibitor with PARP inhibitor or gemcitabine is a novel and rational therapeutic strategy for pancreatic cancer treatment.

Citation Format: Meikuang Chen, Yuan Gao, Dihua Yu, Mien-Chie Hung. MET inhibitor enhances efficacies of gemcitabine and olaparib in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB097.