Abstract 4580: Selective HDAC3 inhibition e-sensitizes PARPi-resistant ovarian cancer cells to olaparib

Abstract

Abstract High-grade serous ovarian cancer is a rare but deadly disease. Platinum-based therapy along with poly ADP ribose polymerase inhibitors (PARPi) maintenance therapy, is recommended to 80% of patients. However, acquired PARPi resistance is an ongoing clinical problem and there is a growing need for the development of more targeted therapies. We have previously shown that the class I histone deacetylase inhibitor (HDACi), entinostat, which is selective for HDAC1/2, resensitizes ovarian cancer cells to PARPi. Here, we propose to examine whether selective inhibition of HDAC3 will induce a synthetic lethality in PARPi-resistant ovarian cancer cells. BRD3308 is an HDACi that is a potent and highly selective inhibitor of HDAC3 and of HDAC1/2 to a lesser extent. To investigate these effects, we used two mouse ovarian cancer epithelial lines ID8 TP53-/-/BRCA2-/- (ID8) and an olaparib resistant line ID8 TP53-/-/BRCA2-/–OR (ID8_OR). We performed cell viability assays (MTS) by treating both cell lines with increasing concentrations of olaparib (0-40uM), BRD3308 (0-2uM), and in combination. When ID8_OR cells were treated with olaparib 5uM and 0.25uM of BRD3308 in combination, cell proliferation was significantly reduced when compared to olaparib treatment alone (p= 0.0077). We did not observe a significant differences in cell proliferation between olaparib alone and in combination with BRD3308 in the ID8 cells. Olaparib and BRD3308 treatment in the ID8_OR cells were found to be synergistic at four out of the five drug concentrations tested, with concentrations 2.5uM olaparib and 0.125 uM of BRD3008 scoring the highest (22, Loewe Synergy Score). In the presence of BRD3308, the olaparib EC50 reduced ~13-folds in the ID8_OR cells compared to only a 2-fold reduction in the ID8 cells. We hypothesizes that inhibition of HDAC3 induces apoptosis by downregulating homologous recombination repair in response to DNA damage. To examine these, we irradiated both ID8 cell lines and treated with olaparib (10 uM), BRD3308 (0.5uM) and in combination, for 24 hours, followed by western blot analysis. Rad51 expression was reduced following combination treatment when compared to control or olaparib alone. Lastly, our clonogenicity data revealed colony formation in both ID8 cell lines were reduced when treated with olaparib (5uM) and BRD3308 (0.25uM). Interestingly, BRD3308 alone reduced colony formation in the ID8_OR cells, but not in the ID8 cells. In conclusion, selective HDAC3 inhibition in combination with olaparib may be an effective therapy in the treatment of acquired PARPi resistant ovarian cancers. Citation Format: Bisiayo E. Fashemi, Vijayalaxmi Gupta, Moreniola Akande, Yukihidi Ota, Sumegha Mitra, Benjamin Bitler, Dineo Khabele. Selective HDAC3 inhibition e-sensitizes PARPi-resistant ovarian cancer cells to olaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4580.