Regorafenib induces DNA damage and enhances PARP inhibitor efficacy in pancreatic ductal carcinoma.

backgroundThere is increasing interest in enhancing the response of the PARP inhibitor olaparib, which is currently approved for pancreatic ductal adenocarcinoma (PDAC) patients with defects in DNA damage repair associated with germline BRCA1/2 mutations. Moreover, agents that can mimic these defects in the absence of germline BRCA1/2 mutations are an area of active research in hopes of increasing the number of patients eligible for treatment with PARP inhibitors. The extent to which regorafenib, an FDA-approved tyrosine kinase inhibitor, can be used to enhance the efficacy of PARP inhibitors in PDAC cells without known BRCA1/2 mutations remains to be investigated.

methodsComet assay, cell cycle analysis, western blotting, and immunofluorescent detection of H2AX

resultsWe now show that regorafenib, a tyrosine-kinase inhibitor with efficacy in several gastrointestinal malignancies, can enhance the response of olaparib in pancreatic cancer. While regorafenib induces DNA damage and limits the ability of PDAC cells to resolve the damage, regorafenib by itself does not induce apoptosis. However, regorafenib in combination with olaparib further induces DNA damage in vitro, in tumor-bearing mice, and in ex vivo slice cultures of human PDAC tumors, resulting in increased apoptosis compared to olaparib alone. Notably, we show that the efficacy of the combination treatment is not dependent on cytolytic T cells.

conclusionsTogether, these findings demonstrate that regorafenib can attenuate DNA damage response and potentiate the efficacy of PARP inhibitors in PDAC tumors.