Abstract 3970: Therapeutic targeting of estrogen receptor positive breast cancer with the BET bromodomain inhibitor ODM-207

Abstract

Abstract Introduction: The bromodomain and extraterminal (BET) family of proteins are chromatin readers that recognize and bind to specific acetylated histones and promote the transcription of several important cell identity genes. BET bromodomain inhibitors have shown promising antitumor activity in a variety of pre-clinical cancer models, as BET inhibition abrogates the transcription of several key oncogenes in a cell type-specific manner. It is known that inhibition of BET proteins effectively inhibits the proliferation of estrogen receptor positive (ER+) breast cancer cells, at least in part through repression of ER and MYC signaling. However, many additional cancer-associated genes are likely to underlie the growth inhibitory effects of BET inhibitors in breast cancer. The purpose of this study was to determine the anticancer activity of the novel BET bromodomain inhibitor ODM-207 in pre-clinical ER+ breast cancer models, and further, to look for cancer-associated signaling pathways suppressed by BET inhibitors. Methodology and results: ODM-207 is a novel, highly selective BET bromodomain inhibitor structurally distinct from JQ1 and its benzodiazepine-related derivatives. In this study, we show that ODM-207 effectively inhibits the proliferation of ER+ breast cancer cell lines when measured by cell viability assays as well as suppresses the growth of patient-derived xenograft tumors. Furthermore, we wanted to investigate the anticancer signaling pathways regulated by ODM-207 as well as the prototypical BET inhibitor JQ1 in breast cancer cells. For this purpose, we performed RNA sequencing on two ER+ breast cancer cell lines after 24h treatment with the aforementioned BET inhibitors. We found that both BET inhibitors targeted several genes and pathways important for breast cancer progression. For example, the targets included CDK4 and CDK6, two cell cycle kinases fundamental for the development and treatment of ER+ breast cancer. The RNA sequencing results were further validated in vitro, and were utilized as a basis for combination therapy assessment. Conclusions: Our results indicate that the novel BET bromodomain inhibitor ODM-207, which is currently in Phase I clinical trials for treating solid tumors, causes significant growth inhibition and cell cycle arrest in pre-clinical models of ER+ breast cancer, and regulates multiple crucial signaling pathways involved in breast cancer cell cycle and survival. Citation Format: Julia Lindqvist, Mari Björkman, Reetta Riikonen, Daniel Nicorici, Elina Mattila, Chandrasekhar Abbineni, Mahaboobi Jaleel, John Eriksson, Pekka Kallio, Anu-Maarit Moilanen. Therapeutic targeting of estrogen receptor positive breast cancer with the BET bromodomain inhibitor ODM-207 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3970.