Abstract 4083: Crizotinib improves the therapeutic efficacy of olaparib in ovarian cancer
Authors: Santiago-O'Farrill Janice M. , Blessing Alicia M. , Becker Sarah E. , Lu Zhen , Bast Robert C. 
Published: September 2020

Abstract
Despite improvements in treatment, ovarian cancer still proves lethal in &gt;60% of cases. One of the most important factors contributing to poor patient outcomes is the ability of dormant ovarian cancer cells to survive following primary surgery and chemotherapy. Poly (ADP) ribose polymerase inhibitors (PARPi) are promising agents for treating both primary and recurrent ovarian cancers. However, acquired drug resistance to PARPi decreases the clinical efficacy of these agents. We have previously found that olaparib induces autophagy in ovarian cancer and the addition of drugs that inhibit autophagy, such as chloroquine, can overcome drug resistance and enhance the anti-cancer activity of PARP inhibitors in ovarian cancer cells, cell line-derived xenograft and patient-derived xenograft models.
Building upon this work, our group has sought drugs that are selectively toxic for autophagic ovarian cancer cells and that might enhance sensitivity to PARP inhibitors. In a previous study, our laboratory had found that knockdown of the anaplastic lymphoma kinase (ALK) significantly reduced survival of ovarian cancer cells that were undergoing autophagy. The FDA-approved ALK inhibitor, crizotinib, exhibited significantly greater toxicity for autophagic ovarian cancer cells in culture and cured a fraction of mice with dormant, autophagic ovarian cancer xenografts. As olaparib induces autophagy in ovarian cancer cells and crizotinib selectively targets autophagic cancer cells, we 1) explored the vulnerability of autophagic cells to the combination treatment of olaparib and crizotinib both in vitro and in vivo; and 2) the mechanism by which the combination of olaparib and crizotinib regulates cell proliferation and programmed cell death.
Enhancement of olaparib activity was observed in 4 ovarian cancer cell lines (OVCAR8, OVCAR3, HEY and SKOV3). Moreover, a combination of olaparib and crizotinib proved more effective than either single agent in a xenograft model of the OVCAR8 ovarian cancer cell line. Mechanistically, a combination of olaparib and crizotinib induces DNA damage and accumulation of γ-H2AX. A combination of olaparib and crizotinib increased reactive oxygen species, while decreasing the phosphorylation of AKT. This decrease in p-AKT was associated with a decrease in p-mTOR, all of which contributed to an increase in autophagy, documented by western blot analysis, LC3 puncta and electron microscopy. Decreased p-AKT also correlated with a decrease in its downstream effector, survivin, leading to apoptosis.
Together, our data suggest that crizotinib can enhance the therapeutic efficacy of olaparib in ovarian cancer by modulating autophagy and apoptosis. Moreover, we have identified a unique combination of therapy with olaparib and crizotinib that could improve the therapeutic efficacy of olaparib and outcomes for ovarian cancer patients.
Citation Format: Janice M. Santiago-O'Farrill, Alicia M. Blessing, Sarah E. Becker, Zhen Lu, Robert C. Bast. Crizotinib improves the therapeutic efficacy of olaparib in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4083.