Abstract NTOC-119: VCP INHIBITORS INDUCE ENDOPLASMIC RETICULUM (ER) STRESS AND SYNERGISTICALLY KILL OVARIAN CANCER CELLS IN COMBINATION WITH SALUBRINAL OR MIFEPRISTONE

Abstract

Abstract Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been linked to several cellular functions including endoplasmic reticulum associated degradation (ERAD), cell division, golgi-membrane reassembly and autophagy. Recent studies have indicated VCP as one of the vulnerabilities in ovarian cancer. Here, we show that treatment with CB-5083, an orally bioavailable compound derived from previously identified quinazoline scaffold-based VCP inhibitor ML240, contributes to cytotoxicity in high-grade serous or clear cell ovarian cancer cell lines. CB-5083 treatment results in increased unfolded protein response (UPR), accumulation of cell cycle proteins as a result of inhibition of proteosomal degradation, cell cycle arrest at G1, and subsequent cell death mediated by both intrinsic and extrinsic apoptotic pathways. These results support an emerging concept that ER stress pathway can be therapeutically targeted in ovarian cancer. Since CB-5083 induces CHOP-dependent apoptosis, we tested the extent to which VCP inhibitors act synergistically with salubrinal, a compound that inhibits GADD34 and enhances eIF2α phosphorylation. Results from Sulforadamine B and clonogenic assays indicate that VCP inhibitors and salubrinal act synergistically across various concentrations of drug combination. Based on recent studies indicating that mifepristone, a steroidal antagonist to progesterone and glucocorticoid, induce ER stress and subsequent cell death, we also tested the potential drug synergies between VCP inhibitors and mifepristone. Our results indicate these drugs act synergistically across various concentrations in ovarian cancer cells. Analysis of TCGA RNA-sequencing datasets indicate VCP expression is down-regulated in cisplatin-resistant tumor samples compared to cisplatin-sensitive cancer. This data is consistent with the fact that tumors with lower expression of VCP shows significant association with poor progression-free survival and overall survivor. Finally, our results indicate that cells with lower expression of VCP are more sensitive to VCP inhibitors than those with higher expression. Considering that cisplatin-resistant tumor samples have lower expression of VCP, VCP inhibitors may be a good therapeutic candidate to treat cisplatin-resistant ovarian cancer. Collectively, our results provide evidence that VCP inhibitors can be used as a single agent and can be synergized with compounds that prolong or induce ER stress in ovarian cancer. Citation Format: Prabhakar Bastola, Frank J. Schoenen, Jeremy Chien. VCP INHIBITORS INDUCE ENDOPLASMIC RETICULUM (ER) STRESS AND SYNERGISTICALLY KILL OVARIAN CANCER CELLS IN COMBINATION WITH SALUBRINAL OR MIFEPRISTONE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-119.