Abstract 5194: Epigenomic and transcriptional profiling of CRC cell lines with distinct response patterns to the BET inhibitor BI 894999

Abstract

Abstract The bromodomain and extra-terminal (BET) protein BRD4 is a “reader” of epigenetic information and binds to acetylated chromatin. BRD4 acts as key regulator of transcriptional elongation by activating P-TEFb at distinct genes. It is via this specific activation of potentially oncogenic transcripts, e.g. MYC, that BRD4 is thought to contribute to tumorigenesis. Inhibition, via so-called BET inhibitors, has indeed proven to be a novel and attractive treatment option tested in ongoing clinical trials for both hematological as well as solid cancers. While BET inhibition shows good efficacy in pre-clinical models of hematological indications, solid tumors show much more heterogeneous responses to monotherapy. Consequently, biomarkers predicting response to treatment with BET inhibitors are of high interest. Colorectal cancer (CRC) is a heterogeneous disease in which novel treatment options are urgently needed. Our pre-clinical studies show that the BET inhibitor BI 894999 is highly active in a fraction of cell lines tested. H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) and transcriptional profiling of sensitive and resistant cell lines identified a small set of H3K27ac peaks associated with sensitivity to BET inhibition. Much of the transcriptional response in CRC cell lines however was cell line specific, leading to only few commonly regulated genes within sensitive versus resistant cell lines. Regarding pharmacodynamic biomarkers in CRC, we could confirm modulation of HEXIM1 after treatment in both sensitive and resistant cell lines. In agreement with previous results (Cohen et al, Nature Comm. 2017), we identified AP1 binding sites in BRD4-bound regulatory regions, which indicates that BRD4 may regulate expression of these genes cooperatively with the transcription factor AP1. Furthermore, the transcription factor TCF4 showed enrichment, suggesting possible interactions between BRD4 and the WNT pathway in a subset of CRC cell lines. The AXIN1, a core WNT pathway component, e.g. is down-regulated in 5/9 cell lines, which however does not track with overall BI 894999 sensitivity. These results, further supporting heterogeneous responses to single-agent BETi treatment, will be discussed. These studies support the further evaluation of BI 894999 as a therapeutic option for colorectal cancer therapy. Citation Format: Fabio Savarese, Daniel Gerlach, Larissa Koller, Susy Straubinger, Paula Elena Träxler, Onur Kaya, Norbert Schweifer, Ulrike Tontsch-Grunt, Norbert Kraut. Epigenomic and transcriptional profiling of CRC cell lines with distinct response patterns to the BET inhibitor BI 894999 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5194.