Abstract 1200: Molecular subtypes of gastric cancer show systematic differences in response to PI3K inhibitors and fluorouracil.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background & Aims: Gastric cancer is the second leading cause of cancer death worldwide, killing >730,000 people every year. Almost all gastric cancers are adenocarcinomas, which exhibit considerable heterogeneity between patients. We sought to identify subtypes of gastric adenocarcinomas that have particular biological properties and responses to cytotoxic drugs. Methods: Robust unsupervised clustering of 248 gastric tumors based on global gene expression revealed three major subtypes. We developed a classifier, GC-Class ("Gastric Cancer Classifier") for the three subtypes and validated it in a second set of 70 tumors. We then determined the distinct genomic and epigenomic properties and drug sensitivities of the subtypes. We determined drug sensitivities of primary tumors by multivariate Cox proportional hazard modeling using clinical survival data. We determined drug sensitivities in cell lines using previously reported data and high-throughput screening of 158 compounds in 23 gastric cancer cell lines. Results: There are three major subtypes of gastric adenocarcinoma: “invasive," “proliferative," and “metabolic”. The subtypes show systematic differences in genomic and epigenetic characteristics and in drug response. Proliferative-subtype tumors show high genomic instability and DNA hypomethylation. Metabolic-subtype cancer cell lines are preferentially sensitive to fluorouracil, and, in two independent groups, patients with the metabolic-subtype tumors benefited significantly from fluorouracil treatment. Invasive-subtype tumors have characteristics in common with cancer stem cells, and cell lines in this subtype are particularly sensitive to PI3K/AKT/mTOR inhibitors. Conclusions: The molecular classification of gastric cancers reported here is reproducible and biologically and therapeutically meaningful, and it holds promise as a basis for selecting and developing therapies tailored to particular subtypes. Citation Format: Zengdeng Lei, Nian Tao Deng, Hermioni Zouridis, Iain Beehaut Tan, Chia Huey Ooi, Tatiana Ivanova, Shenli Zhang, Minghui Lee, Jeanie Wu, Anna Ngo, Sravanthy Manesh, Alex Boussioutas, Bin Tean Teh, Liang Kee Goh, Horst Flotow, Patrick Tan, Steven G. Rozen. Molecular subtypes of gastric cancer show systematic differences in response to PI3K inhibitors and fluorouracil. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1200. doi:10.1158/1538-7445.AM2013-1200