Tumor Treating Fields (TTFields) Concomitant with PARP Inhibitors for Treatment of Ovarian Cancer Cell Lines

Abstract

<h3>Purpose/Objective(s)</h3> TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. Recently, TTFields have also been shown to induce a state of BRCAness in various cancer types. PARP inhibitors (PARPi) demonstrate clinical efficacy in patients with solid tumors and deleterious BRCA mutations; however, 3 of 4 patients with ovarian cancer do not harbor BRCA mutations, and thus may experience limited benefit from PARP inhibition. TTFields have shown in vitro and in vivo efficacy in ovarian cancer models. The objective of this study was to examine the effect of TTFields concomitant with PARPi on ovarian cancer cell lines. <h3>Materials/Methods</h3> A2780 (BRCA1/2 wild type) and OVCAR3 (BRCA1 wild type, BRCA2 deep deletion) ovarian carcinoma cells were treated for 72 h with TTFields at an intensity of 1 V/cm RMS and frequency of 200 kHz, alone or with concomitant application of the PARP inhibitors niraparib or olaparib. Efficacy was examined via measurements of cell survival, colony forming ability, and induction of apoptosis. Formation of DNA double strand breaks was examined by fluorescence staining for ɣH2AX. <h3>Results</h3> Application of TTFields or PARPi to A2780 or OVCAR3 cells resulted in cytotoxicity, anti-clonogenic effect, and induction of apoptosis. Concomitant application of TTFields with PARPi displayed synergistic interaction in the BRCA wild type A2780 cells and additively in the BRCA mutant OVCAR-3 cells. Co-application of TTFields and PARPi also resulted in increased levels of DNA double strand breaks in both cell lines relative to each modality alone. <h3>Conclusion</h3> The results support that TTFields induce a state of BRCAness, which together with PARP inhibition can possibly lead to synthetic lethality. Collectively, the data suggest potential benefits for TTFields concomitant application with PARP inhibition for treatment of ovarian cancer even in the absence of background BRCA mutations.