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Pharmacogenomic Identification of Novel Determinants of Response to Chemotherapy in Colon Cancer

¹ Department of Oncology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland; ² Almac Diagnostics Ltd., Seagoe Industrial Estate, Craigavon, Northern Ireland; and ³ Department of Oncology, Hutchinson/Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom

Requests for reprints: Patrick G. Johnston, Department of Oncology, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast City Hospital, University Floor, Lisburn Road, Belfast, BT9 7AB, Northern Ireland. Phone: 44-28-90263911; Fax: 44-28-90263744; E-mail: oncology{at}qub.ac.uk.

DNA microarray analysis was used to analyze the transcriptional profile of HCT116 colorectal cancer cells that were treated with 5-fluorouracil (5-FU) or oxaliplatin and selected for resistance to these agents. Bioinformatic analyses identified sets of genes that were constitutively dysregulated in drug-resistant cells and transiently altered following acute exposure of parental cells to drug. We propose that these genes may represent molecular signatures of sensitivity to 5-FU and oxaliplatin. Using real-time reverse transcription-PCR (RT-PCR), the robustness of our microarray data was shown with a strong overall concordance of expression trends for 82% (oxaliplatin) and 85% (5-FU) of a representative subset of genes. Furthermore, strong correlations between the microarray and real-time RT-PCR measurements of average fold changes in gene expression were observed for both the 5-FU (R² 0.73) and oxaliplatin gene sets (R² 0.63). Functional analysis of three genes identified in the microarray study [prostate-derived factor (PDF), calretinin, and spermidine/spermine N¹-acetyl transferase (SSAT)] revealed their importance as novel regulators of cytotoxic drug response. These data show the power of this novel microarray-based approach to identify genes which may be important markers of response to treatment and/or targets for therapeutic intervention. (Cancer Res 2006; 66(5): 2765-77)

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