The combination of a BET and poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors decreased pancreatic ductal adenocarcinoma (PDAC) growth in preclinical models and may provide a novel approach to treatment, according to a study presented at the 2018 AACR Pancreatic Cancer: Advances in Science and Clinical Care conference in Boston, Massachusetts.1
Prior studies have suggested that the BET inhibitor JQ1 downregulates the expression of BET-dependent genes. Though JQ1 decreases PDAC tumor growth in animal models, the responses are not durable when it is used as monotherapy. Other studies also have suggested that JQ1 promotes DNA damage by inhibiting DNA repair, causing DNA repair deficiency. Therefore, the investigators hypothesized that the JQ1 would sensitize PDAC tumor cells to the PARP inhibitor olaparib.
This study treated 2 independent animal models with JQ1 plus olaparib; JQ1 or olaparib monotherapy; or vehicle control.
JQ1 plus olaparib significantly decreased PDAC tumor growth compared with JQ1 or olaparib monotherapy (P < .0001) or vehicle control (P < .05). There was an 8- to 33-fold increase in JQ1-induced DNA damage and a 54% to 90% inhibition of Ku80 and Rad51 with the combination treatment, as determined by immunoblot and immunohistochemistry analyses.
The investigators concluded that these data suggest that “combining a BET inhibitor with a PARP inhibitor may represent a novel approach for the treatment of PDAC.”
- Miller A, Fehling SC, Gamblin TL, et al. Combining the BET inhibitor JQ1 with the PARP inhibitor olaparib as a potential treatment for pancreatic ductal adenocarcinoma. Presented at: AACR Pancreatic Cancer: Advances in Science and Clinical Care; September 21-24, 2018; Boston, Massachusetts. Abstract A066.