Abstract 4013: CoA Synthase (COASY): A novel predictive marker and functional protein that mediates radiation resistance via PI3K signaling in rectal cancer

Abstract

Abstract Purpose: Rectal cancer response to neoadjuvant chemoradiation is prognostic for disease-free and overall survival, with better responders enjoying better outcomes. Understanding the biology underlying better responses to therapy could lead to more personalized treatment approaches. The purpose of this study was to evaluate a newly identified biomarker and explore its mechanism of action. Experimental Design: Pretreatment human rectal cancer samples underwent DNA microarray analysis and profiles were compared to post-chemoradiation histologic regression scores. A candidate gene, COASY (which encodes for Coenzyme A Synthase), was stably knocked down by shRNA in colorectal cell lines, and the effects on response to radiation were tested in a xenograft model. The biological function of COASY was first assessed by Gene Set Enrichment Assay (GSEA). Its effects on cell death, cell survival, and DNA repair capacity in colorectal cell lines was analyzed. Immunoprecipitation of COASY followed by LC-MS/MS analysis was done to identify COASY partners. Results: COASY gene expression was overexpressed in rectal cancer compared to normal rectum and was significantly correlated to the tumor regression score. Tumors from cell lines knocked down for COASY had a strong delayed tumor growth, less proliferation, and more apoptosis after irradiation than the control cell line using in vivo xenograft models. In addition, a higher cell death rate after irradiation was observed in vitro in two colorectal cancer cell lines knocked down for COASY. Mechanistically, a physical interaction between COASY and the PI3K regulatory subunit PI3K-P85α was identified; which led to a modulation of AKT and mTOR phosphorylation after irradiation. Furthermore, there were more residual double DNA strand breaks after irradiation in cell lines knocked down for COASY accompanied by a decrease in DNA-PK and MRE11 protein levels. Conclusion: COASY serves as a predictive biomarker for rectal cancer response to neoadjuvant chemoradiation and its increased levels correlate with poor response. In addition to its role as a predictive biomarker, COASY has biological relevance leading to increased radiation resistance via the PI3K pathway-dependent increase in DNA repair capacity. Citation Format: Sylvain Ferrandon, Jennifer DeVecchio, Leonardo Duares, Hanuman Chouhan, Jacqueline Davenport, Georgios Karagkounis, Matthew Orloff, David Liska, Matthew F. Kalady. CoA Synthase (COASY): A novel predictive marker and functional protein that mediates radiation resistance via PI3K signaling in rectal cancer [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 4013.