Abstract 5824: The BET inhibitor JQ1 sensitizes cholangiocarcinoma cells to PARP inhibitors
Authors: Fehling Samuel C. , Miller Aubrey L. , Bradner James E. , Yoon Karina J. 
Published: August 2018

Abstract
Cholangiocarcinoma (CCA) is an aggressive bile duct neoplasm, and the second most common primary hepatic malignancy. CCA is usually diagnosed at a late stage where the current standard of care, resection followed by gemcitabine with or without cisplatin, is not effective. Up to 90% of CCA patients are ineligible for resection and, of those eligible, postoperative chemotherapy does not significantly prolong overall survival. The limited number of CCA models hinders drug development and discovery of new therapeutic targets. Mutations have been identified in KRAS (17% of CCA tumors), p53 (44%) and SMAD4 (17%), but are not recognized as essential to CCA progression. c-Myc protein is highly expressed in 94% of CCA cases while low to undetectable in normal adult liver, suggesting c-Myc overexpression may contribute to CCA tumor progression but this hypothesis has not been tested. Toward developing novel effective therapies for CCA, we evaluated the effect of the bromodomain and extraterminal domain (BET) inhibitor JQ1 on c-Myc expression and on the proliferation of CCA cells. JQ1 inhibits c-Myc transcription by binding to the acetylated lysine (K-Ac) binding pockets of BET protein family members (BRD2, BRD3, BRD4 and BRDT), preventing their interaction with K-Ac residues on nuclear proteins, disrupting the formation of functional transcriptional complexes and inhibiting c-Myc transcription. We have shown that JQ1 inhibited tumor growth in a patient-derived xenograft (PDX) model of CCA and downregulated expression of c-Myc and its transcriptional targets BRCA2 and Chk1, both involved in DNA damage response. Our current data show that JQ1 decreased c-Myc protein expression, CCA cell viability, and clonogenic potential in KKU-055 CCA cell line. Of note, the literature suggests that tumors deficient in BRCA2 or Chk1 are relatively sensitive to PARP inhibitors (PARPi). Therefore, we hypothesize that JQ1-induced downregulation of c-Myc and its transcriptional targets BRCA2 and Chk1 would potentiate the efficacy of PARPi. We exposed CCA cell line KKU-055 with a range of JQ1 and PARPi (olaparib and veliparib) concentrations as single agent or combination therapy. Each combination of JQ1 with either PARPi was more effective than any of the three drugs as single agents. Combination indices (CI), calculated using CompuSyn 1.0, ranged from 0.05 to 0.09 which indicated strong synergy for JQ1 with olaparib or veliparib. Further, synergy with JQ1 was not dependent on a single PARPi. JQ1 with olaparib (1:1) also decreased the clonogenic potential of KKU-055 cells, compared to each drug as a single agent. These data suggest that inhibition of BET protein function sensitizes CCA cells to PARPi, coincident with downregulation of c-Myc and its transcriptional targets BRCA2 and Chk1. Research funded by NIH/NCI R21 CA205501
Citation Format: Samuel C. Fehling, Aubrey L. Miller, James E. Bradner, Karina J. Yoon. The BET inhibitor JQ1 sensitizes cholangiocarcinoma cells to PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5824.