Abstract 5069: Inhibition of BET bromodomain, epigenetic regulator, as an effective therapeutic approach for gastric cancer
Authors: Kang Sun Kyoung , Kim Tae Soo , Kwon Woo Sun , Roh Jae Kyung , Lim Ho-Yeong , Chun Hyun Cheol , Rha Sun Young 
Published: July 2017

Epigenetic dysregulation is a common characteristic of cancer, including gastric cancer(GC), which ultimately contributes to the development and progression of GC. Sequencing of cancer genomes has revealed frequent mutations in epigenetic regulators, particularly chromatin remodelers and histone modifiers, and disordered chromatin regulation has emerged as a distinct mechanism contributing to tumor development. As a highly conserved class of epigenome readers, BRD4 is a member of the BET (bromodomain and extra-terminal domain) family that recognizes and binds acetylated histones H3 and H4 and influences gene regulation. Small molecule BET inhibitors prevent binding of BET proteins to acetylated histones and inhibit transcriptional activation of BET target genes. BET inhibitors attenuate cell growth and survival in several hematologic cancer models, partially through the down-regulation of the critical oncogene, c-Myc. We would like to elucidate the sensitivity to I-BET151 and its relationship with genetic/epigenetic alterations to identify predictive biomarkers in 49 gastric cancer cell lines. Anticancer effect of small molecular inhibitor of the BET family, GSK1210151A (I-BET151, GSK, PA, USA), was treated for 6 days and assessed using CCK-8 assay. For exploring predictive biomarkers, we analyzed genetic and molecular characterization of BRD4-related genes using whole exome sequencing (WES), RNA sequencing and western blots. As a result, ARID1A deletion (SNU-5 and YCC-6) and single nucleotide variant (14/49, 28.5%) were correlated with decreased protein expression (p&lt;0.0001). However, these ARID1A variants were not related to sensitivity of I-BET151. While, BRD4 was expressed in almost cell lines with no mutations. When we screened 49 cell lines for growth inhibition by I-BET151 and 73%(36) of cells showed modest activity to I-BET-151. We divided into two groups according to the sensitivity: extremely sensitive (IC50 &lt; 1 uM: 13 cell lines) and extremely resistant (IC50 &gt; 5 uM: 13 cell lines). Then, we analyzed Differentially Expressed Gene (DEG) in each group and selected about 600 genes (FDR &lt; 0.05, p &lt; 0.001 and 1.5 fold) including CXCL5, HRK, BMPER and IGDCC4. BRD4 mRNA expression was lower in extremely sensitive group compared to extremely resistant group (p = 0.0163), but BRD4 protein expression was not. In addition, no association has been observed between other genes expression, such as MYC, BCL2, HEXIM1/2, SRC, TXNIP, CCND1 and MLKL, and sensitivity to I-BET151. Our data indicates that I-BET151 is a potent inhibitor of GC and showed the possibility of development a predictive biomarker based on genetic and molecular profiling.

Citation Format: Sun Kyoung Kang, Tae Soo Kim, Woo Sun Kwon, Jae Kyung Roh, Ho-Yeong Lim, Hyun Cheol Chun, Sun Young Rha. Inhibition of BET bromodomain, epigenetic regulator, as an effective therapeutic approach for gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5069. doi:10.1158/1538-7445.AM2017-5069