Treatment resistance of rectal cancers: identification and functional validation of novel therapeutic targets

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We recently demonstrated that gene expression profiling might be useful for predicting the response of rectal carcinomas to preoperative chemoradiotherapy (CT/RT). Based on T-level downsizing, 54 genes showed significantly different expression levels between responders and nonresponders. While a major objective of subproject 1 is to prospectively validate this gene set in a much larger cohort of patients, the present subproject aims to functionally validate these genes by modifying their expression levels in cancer cell lines. We will therefore screen established CRC (colorectal cancer) cell lines to identify those cell lines with high expression levels for genes which were upregulated in resistant primary tumors. The functional validation will be pursued by RNA interference-mediated knockdown and assessment of the consequences of this knockdown relative to exposure to CT/RT. These experiments will be supported by establishing cell lines from responsive and resistant rectal adenocarcinomas. We anticipate that this process of functional validation will unveil relevant pathways for resistance to CT/RT. This would be a first step toward identifying small molecules that modify these pathways such that a priori resistant cell lines, and eventually primary tumors, could be sensitized to CT/RT in vitro.