Abstract 5792: Preclinical antitumor activity of BMS-986158, an oral BET inhibitor, for the treatment of cancer
Authors: Wee Susan , Jackson Donald , Desilva Heshani , Dajee Maya , Carman Julie , Ross-MacDonald Petra , Gan Jinping , Westhouse Richard A. , Huang Christine , Yang Zheng , Poss Michael , Hunt John T. , Vite Gregory D. , Gavai Ashvinikumar V. 
Published: August 2018

Abstract
Background: Regulation and recognition of covalent chromatin modifications by cellular proteins are key determinants of gene expression. Bromodomain and extra-terminal (BET) proteins, including BRD2, BRD3, BRD4, and BRDT, bind directly to acetylated lysine on histone tails to promote gene transcription. Oncogenes such as c-MYC, BCL2, and ASCL1, are directly regulated by BET proteins. Here, we report the preclinical evaluation of BMS-986158, an orally bioavailable, potent, and selective BET inhibitor.
Methods: BMS-986158 activity was assessed in tumor growth assays across solid and hematologic cancer cell lines in vitro and in vivo in patient-derived xenografts (PDX). Dose-response gene expression profiling of ex vivo blood from healthy donors was used to identify transcripts exhibiting a pharmacodynamic effect with BMS-986158 treatment.
Results: Tumor growth inhibition (TGI) with BMS-986158 was observed across different solid and hematologic cancer cell lines. Mutations in chromatin regulators were identified among BMS-986158–sensitive cell lines. BMS-986158 also demonstrated antitumor activity (TGI ≥ 70%) in 24 of 82 PDX models tested (Table). Genetic alterations that correlate with BMS-986158 responsiveness will be presented. Finally, an ex vivo dose-response profiling study in healthy human blood identified 124 genes responsive to BMS-986158, including chemokines and chemokine receptors.
Conclusions: BMS-986158, a potent and selective BET inhibitor, demonstrated robust anti-proliferative activity in vitro across a broad range of cancer cell lines. Consistent with the in vitro data, preclinical antitumor activity was observed in various PDX tumor models. Furthermore, gene expression profiling studies in human blood samples identified select target genes responsive to BMS-986158 treatment that may be useful as clinical pharmacodynamic markers.
TGI assay in PDX modelsTumor TypeTotal sample, nResponders, naAdenocarcinoma319Lung squamous cell carcinoma217Breast cancer82Brain cancer10Colorectal cancer63Esophageal cancer31Gallbladder cancer21Head and neck cancer31Mixedb70Total8224a Responders were defined as having &gt; 70% TGIb Mixed tumor types include large cell neuroendocrine carcinoma of the lung, liver, liver metastases from rectum, mixed adenocarcinoma, neuroendocrine tumor, and non-small cell lung cancer
Citation Format: Susan Wee, Donald Jackson, Heshani Desilva, Maya Dajee, Julie Carman, Petra Ross-MacDonald, Jinping Gan, Richard A. Westhouse, Christine Huang, Zheng Yang, Michael Poss, John T. Hunt, Gregory D. Vite, Ashvinikumar V. Gavai. Preclinical antitumor activity of BMS-986158, an oral BET inhibitor, for the treatment of cancer [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 5792.