Crizotinib and PARP inhibitors act synergistically by triggering apoptosis in high-grade serous ovarian cancer

Abstract

High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherapy and olaparib, niraparib (Zejula™) and rucaparib (Rubraca™) are approved as maintenance therapies in the recurrent, platinum-sensitive setting; nevertheless, development of resistance limits their efficacy. In this study, new combinatorial treatment strategies targeting key signaling pathways were explored to enhance the activity of PARP inhibitors in HGSOC. Carboplatin, olaparib, niraparib, the PI3K inhibitor LY294002 and the c-Met inhibitor crizotinib were used for this investigation. PARP inhibitors and carboplatin alone and in combination caused accumulation of DNA double-strand breaks and G2/M cell cycle arrest. In contrast, crizotinib alone or in combination with PARP inhibitors induced accumulation of cells in sub-G1. Crizotinib together with either of the PARP inhibitors was more strongly synergistic than combinations with a PARP inhibitor and carboplatin or the PI3K inhibitor. Sequential combination of crizotinib and a PARP inhibitor resulted in activation of ATM/CHK2 and inhibition of c-Met pathways, contributing to a decrease in RAD51 levels and induction of caspase-3 dependent apoptotic cell death and suggesting that the combination of crizotinib with a PARP inhibitor may be considered and further explored as a new therapeutic strategy in HGSOC.

MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer

“…Synergistic effects of olaparib and the c-MET inhibitor crizotinib have been reported in earlier studies, including ours [ 15 , 16 , 17 ], but the benefit of combining PARPi and METi could not be verified in the cell lines representing treatment resistance used in the present study. Crizotinib also inhibits ALK and ROS1, in addition to MET, but possible effects on downstream signaling in these pathways were not further explored in this study, as all four cell lines lacked the expression of ALK and ROS1.…”

“…Several studies report that MET can phosphorylate PARP1, thereby preventing binding of the inhibitor and thus making cells PARPi-resistant [ 13 , 14 ]. The combination of a MET inhibitor (METi) and a PARPi has been shown to synergistically inhibit growth in TNBC cell lines [ 15 ] as well as in ovarian cancer cell lines [ 15 , 16 , 17 ].…”

Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines

“…Metformin at 20 mM increases the level of cleaved caspase-3 in SKOV-3 and Hey cell lines [ 83 ]. Olaparib at 5 μM slightly increased the cleavage of caspase-3 in high-grade serous ovarian carcinoma cells [ 84 ]. However, reports also show that the combination of metformin and olaparib does not induce marked apoptosis in BRCA1-intact ovarian cancer cells, although cell-cycle analysis revealed a significant S-phase arrest.…”

Targeting c-MET to Enhance the Efficacy of Olaparib in Prostate Cancer

“…18,19 In previous studies, c-MET inhibition increased sensitivity to olaparib in triple-negative breast cancer cells with acquired resistance to PARPi, 20 and in breast cancer, lung cancer, 11 and ovarian cancer. 21 However, it is unclear whether the combination of c-MET and PARP-1 inhibitors results in synergistic suppression of the growth of PCa. In the current study, c-MET inhibition by PHA665752 significantly increased sensitivity to olaparib in both the CRPC cell line DU145 and the hormone-sensitive PCa cell line LNCaP.…”