Abstract NT-111: THE ANTIPROGESTIN/ANTIGLUCOCORTICOID MIFEPRISTONE AND THE HIV PROTEASE INHIBITOR NELFINAVIR CAUSE ENDOPLASMIC RETICULUM STRESS AND POTENTIATE THE TOXICITY OF PROTEASOME INHIBITION IN HIGH-GRADE SEROUS EPITHELIAL OVARIAN CANCER CELLS
Authors: Mahbuba Subeha, Lei Zhang, Alicia Goyeneche, Carlos Telleria
Journal: Clinical Cancer Research (2019)

Abstract Epithelial ovarian cancer (EOC) is a fatal disease due to late diagnosis and lack of effective long-term treatment(s). Since the introduction of debulking surgery and platinum (Pt)-taxane (Tx) therapy over 30 yrs. ago, there has been no significant breakthrough impacting the overall survival of these patients. Though over 70% of diagnosed women respond to front-line standard of care with remission, the disease hides as microscopic (minimal residual) within the abdominal cavity for about 18-24 months (mo.), recurring thereafter with a phenotype usually not responsive to current chemotherapeutic agents. As patients are left without treatment between remission and recurrence, our research initiative is to develop a consolidation therapy for chronic use after standard of care. In this work we explored whether such consolidation therapy could be developed from two simultaneous strategies: proteasome inhibition and aggravation of the stress of the endoplasmic reticulum (ER). The rationale for this combination therapy is that malignant cells are more susceptible to the toxicity of proteasome inhibition and operate with increased expression of ER stress-related proteins—coined as unfolded protein response (UPR) addiction—allowing cancer cells to survive in a hostile environment of reduced nutrients, acidosis, energy deficiency, and low oxygen tension (hypoxia). We hypothesized that simultaneous ER stress aggravation and blockage of the proteolytic capacity of the proteasome should cause sufficient ER stress to tilt cells to a death fate. We report that antiprogestin/antiglucocorticoid mifepristone (MF) as well as HIV protease inhibitor nelfinavir (NFV) enhanced the stress of the ER in EOC cells of high-grade serous origin (HGSOC), which is the most aggressive subtype of EOC, represents the majority of cases of EOC, and causes 2/3 of all deaths from this disease. We demonstrated, in HGSOC cells, that both MF and NFV cause cell cycle arrest associated with increased expression of cyclin dependent kinase inhibitor p27kip1, while triggering the UPR in a dose-dependent manner assessed by increased subrogate ER stress biomarkers GRP78, ATF4, and CHOP. We also discovered that blocking the ubiquitin proteasome system (UPS) using cytostatic concentrations of the proteasome inhibitor bortezomib (BZ) causes accumulation of poly-ubiquitinated proteins and further activation of the UPR. More importantly, when we combined BZ with either MF or NFV, we observed a potentiation of the action of BZ leading to EOC lethality. These results suggest that targeting the ER stress-associated protein quality control machinery with either an antiprogestin/antiglucocorticoid agent or an HIV protease inhibitor may provide an alternative chronic treatment approach against HGSOC after standard of care. In addition, the data provide the rationale for rapid repurposing to treating HGSOC, of three drugs clinically approved for other uses, as their systemic toxicities have already been assessed. Citation Format: Mahbuba Subeha, Lei Zhang, Alicia Goyeneche, Carlos Telleria. THE ANTIPROGESTIN/ANTIGLUCOCORTICOID MIFEPRISTONE AND THE HIV PROTEASE INHIBITOR NELFINAVIR CAUSE ENDOPLASMIC RETICULUM STRESS AND POTENTIATE THE TOXICITY OF PROTEASOME INHIBITION IN HIGH-GRADE SEROUS EPITHELIAL OVARIAN CANCER CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-111.