Abstract 1781: Identification of focal adhesion and actin cytoskeleton regulation family genes as druggable target for gastric cancer

Abstract

Abstract Gastric cancer(GC) is the 4th most common malignancy in the world and the 2nd most common cause of cancer related death worldwide (1). The known causes of GC are diet, hygiene, Helicobacter pylori, Epstein-Barr virus and hereditary factors. Other genetic causes of GC are known to be heterogenic, partially due to differences in ethnic/genetic background. Surgical removal of the tumor is the first-line treatment. Targeted therapy agents and chemotherapeutic agents that show survival advantage in other cancer types are being evaluated in GC(2,3), which only target few known oncogenes. Targeted therapy for GC is still an unmet need, and in light of personalized medicine, identifying genes specific to GC is critical for its treatment. From our NGS data, we have discovered protein family members involved in focal adhesion and actin cytoskeleton regulation pathways, which are involved in mitosis and metastasis. We developed a subpathway network analysis method called PATHOME(unpublished), to identify pathways related to GC. For the first stage, two datasets (84 Korean GC: GSE13861 and 56 Japanese GC:GSE15081)(4,5). Two datasets (25 Korean GC: GSE36968 and 160 Chinese GC:GSE27342)(6,7,8) were used as validation sets. We identified top 10 common pathways. We have then categorized genes within these pathways according their functional category and druggability, either as drug transporter or druggable target. As a result, we identified genes involved in the focal adhesion and regulation of actin cytoskeleton pathways and cell junction, all critical for cell division and metastasis of tumor cells. Genes G1-9 are tight junction genes, and G10-20 are protein family group related to Ras-like GTP-binding protein, G10 - 20. G10, 11 and 12 are ras-like GTPases, and G13-20 are interacting proteins or downstream proteins. We then compared differential expression of these genes between the Asian and Caucasian dataset. G1-9 show co-regulation pattern among the two ethnic group. G9 in particular, is normally expressed in the stomach, and is downregulated (p=0.0045) in GC tumor samples. In contrast, G10 is upregulated in the Korean dataset and is shown to be upregulated in Japanese and Chinese GC sample (public) as well(9,10), but not in our Caucasian dataset(unpublished). The TCGA stomach cancer provisional data via cBioPortal(11) shows that most of the G10 alterations in GC cases are mutations (9% of total cases) with 2 known cases of downregulation. It is interesting that most of the G10 alterations were found in Caucasian patients (11/18 cases). In our study, we have identified genes that are significant in GC and are druggable targets/drug transporters. It is significant that the pathways we identified are detected in both ethnic groups, with different expression pattern. This finding is critical for personalized treatment and drug development for GC. Citation Format: Hae Ryung Chang, Seungyoon Nam, Myeong-Cherl Kook, Hee Seo Park, Hae Rim Jung, Youme Gim, Han Liang, Garth Powis, Yon Hui Kim. Identification of focal adhesion and actin cytoskeleton regulation family genes as druggable target for gastric cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1781. doi:10.1158/1538-7445.AM2014-1781