Abstract 1378: Targeting the metabolic-epigenetic axis to sensitize HR-proficient ovarian cancer to PARP inhibitors

Abstract

Abstract Overexpression of the oncogene cyclin E1 is considered one of the initiating factors in fallopian tube transformation and ovarian tumorigenesis. Patients with high cyclin E1 expression have worse overall survival than patients with low expression. Cyclin E1 overexpression increases expression of DNA damage response (DDR) genes in order to tolerate DNA damage and bypass senescence, a state of cell cycle arrest. However, the mechanism by which cyclin E1-high cells transcriptionally increase DDR gene expression to bypass senescence remains unclear. We found that cyclin E1 overexpression alters the metabolic-epigenetic axis through wildtype isocitrate dehydrogenase I (wtIDH1), a TCA cycle enzyme. Upregulation of wtIDH1 in cyclin E1-high cells increased the transcription of multiple DDR genes related to homologous recombination (HR), including BRCA1, BRCA2, and RAD51. Published data from our lab demonstrates that wtIDH1 primarily converts isocitrate to alpha-ketoglutarate (αKG) in cyclin E1-high ovarian cancer cells, and suppression of wtIDH1 and αKG pools induces senescence through increased repressive histone marks. Our current data suggest that wtIDH1 is both necessary and sufficient for HR gene expression in cyclin E1-high cells in part through modulation of histone methylation. Functionally, inhibition of wtIDH1 in cyclin E1-high fallopian tube cells induced senescence via decreased HR and marked accumulation of DNA damage. Cyclin E1-high ovarian cancer tumors are HR-proficient and resistant to emerging poly(ADP-ribose) polymerase (PARP) inhibitors. Interestingly, inhibition of both wtIDH1 and PARP in combination increased apoptosis of cyclin E1-high ovarian cancer cells in vitro, suggesting this may be a novel therapy for HR-proficient ovarian cancers. Together, our data suggest that wtIDH1-mediated metabolism affects the epigenome in cyclin E1-high cells, which contributes to both fallopian tube transformation and HR-proficiency. Targeting wtIDH1 with current FDA-approved inhibitors may therefore be a rational therapeutic strategy for cyclin E1-high ovarian cancer patients. Citation Format: Erika S. Dahl, Kelly E. Leon, Chi-Wei Chen, Qingyuan Jia, Raquel Buj, Nathaniel W. Snyder, Katherine M. Aird. Targeting the metabolic-epigenetic axis to sensitize HR-proficient ovarian cancer to PARP inhibitors [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 1378.