Abstract 2508: Identification of potential relevant pathways and genes for resistance to chemoradiotherapy in colorectal cancer cells

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL The standard treatment of patients with locally advanced rectal cancers comprises preoperative 5-fluorouracil-based chemoradiotherapy followed by standardized surgery. However, the tumor response to multimodal treatment has varied greatly and ranging from complete resistance to complete pathologic regression. The prediction and treatment of these observed heterogeneous response to therapy in patients is, therefore, an important clinical need. A strategy for studying the molecular basis of this heterogeneous tumor response is to establish the clinical parameters as an in vitro model. For this purpose we used 12 colorectal cancer cell lines and exposed them to 3 µM of 5-fluorouracil and 2 Gy of radiation, which reflect the parameters used in clinical patient treatment. The sensitivity differences of the cell lines to chemoradiotherapy, measured as surviving fractions by a standard colony formation assay, were then correlated with the pretherapeutic gene expression profiles of these cell lines. The microarray measurements were independently validated for a subset of these genes using real-time polymerase chain reactions. In the 12 colorectal cancer cell lines we observed a heterogeneous response, with surviving fractions ranging from 0.28 to 0.81, closely recapitulating clinical reality. Using a linear model analysis, we identified 4,796 features whose expression levels correlated significantly with the sensitivity to chemoradiotherapy (Q < 0.05), including many genes involved in the mitogen-activated protein kinase signaling pathway or cell cycle genes. These data have suggested a potential relevance of the insulin and Wnt signaling pathways for the treatment response, and we identified STAT3, RASSF1, DOK3, and ERBB2 as potential therapeutic targets. We anticipate that this analysis of a gene expression signature for the in vitro chemoradiosensitivity of colorectal cancer cells will unveil molecular biomarkers predictive of the response of rectal cancers to chemoradiotherapy and enable the identification of genes that could serve as targets to sensitize a priori resistant primary tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2508. doi:10.1158/1538-7445.AM2011-2508