Abstract 2060: Therapeutic approaches for CCNE1-amplified HR-proficient ovarian cancer

Abstract

Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors have shown great success in ovarian cancer patients that are homologous recombination deficient (HRD). However, approximately 50% of high grade serous ovarian cancer (HGSOC) are HR-proficient. HR-proficient Cancer cells evade lethal DNA damage by triggering HR pathways at the cost of genome stability and evolving of more aggressive cancer cells. Cyclin E1 (CCNE1) amplification is a major subset of known HR-proficient HGSOC. This subset of cancer responds poorly to essentially all available ovarian cancer therapies including PARP inhibitors. Our study showed that the mTOR, HR, and checkpoint pathways were enriched in CCNE1-amplifed ovarian cancer patients. Interactome mapping demonstrated that many of the interactive proteins in the mTOR pathway were also components of HR and DNA checkpoint pathways. mTOR inhibition resulted in downregulation of HR and DNA checkpoint proteins. Downregulation of ATR partly mirrored mTOR inhibition. mTOR inhibitors and ATR inhibitors synergized with PARP inhibitors in vitro and in vivo in CCNE1-amplified HGSOC tumors. This was associated with decrease in cancer stem-like cancer cells and loss of polyploid tumor cells, which are vital for evolving of more aggressive, therapy-resistant cancer cells. These studies will have potential impact on further preclinical validation and clinical applications to cure CCNE1-amplifed HRP ovarian cancer. Citation Format: Shoumei Bai, Ronald J. Buckanovich. Therapeutic approaches for CCNE1-amplified HR-proficient ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2060.