The Bet Inhibitor Incb054329 Is Efficacious As A Single Agent Or In Combination With Targeted Agents In Colorectal Cancer Models

The Bromodomain and extra-terminal (BET) family of proteins consists of BRD2, BRD3, BRD4 and BRDT. Each BET protein contains two bromodomains (BD1 and BD2) that recognize acetylated histones at enhancer and promoter regions of a select number of genes. BET proteins function as transcriptional regulators that are critical for the expression of oncogenes such as c-Myc; thus, BET proteins are important for cancer cell proliferation and survival. We have identified INCB054329, a potent and selective BET protein inhibitor that targets BD1 and BD2 of BRD2, BRD3 and BRD4. In this study, we characterized the pharmacology of INCB054329 in solid tumor cell lines. In a panel of colon cancer cell lines, more than 50% are sensitive to INCB054329 treatment with IC50 values below 500 nM in cell proliferation assays. INCB054329 down-regulated c-Myc expression, and induced cell cycle arrest and apoptosis in sensitive colon cancer cell lines. Moreover, INCB54329 was efficacious in the RKO colon cancer xenograft model. To understand whether BRD inhibition would synergize with other signaling pathway inhibitors and standard of care agents for colon cancer, we employed a high throughput combination screening strategy. Several combinations were active in a panel of colon cancer cell lines and demonstrated synergistic interactions based on combination index values. As an example, strong synergy was observed between INCB054329 and MEK inhibitors. The combination of INCB054329 and MEK inhibitors synergistically blocked expression of c-Myc protein and inhibited the MEK/ERK signaling pathway. Our data suggest the potential utilization of INCB054329 as a single agent or in combination with other targeted therapies for the treatment of colon cancer. Citation Format: Xuesong Liu, Jun Li, Xin He, Matthew Stubbs, Margaret Favata, Xiaoming Wen, Hong Chang, Beth R. Rumberger, Yanlong Li, Thomas Maduskuie, Richard Sparks, Nikoo Falahatpisheh, Padmaja Polam, Andrew P. Combs, Reid Huber, Gregory Hollis, Peggy Scherle, Phillip C. Liu. The BET inhibitor INCB054329 is efficacious as a single agent or in combination with targeted agents in colorectal cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3525. doi:10.1158/1538-7445.AM2015-3525