Pathway determinants of 5-fluorouracil sensitivity

Abstract

We describe here a pathway-based gene expression analysis in determining 5-Fluorouracil (5FU) sensitivity in cell lines, xenografts and tumours. The expression of 96 rationally-selected genes was measured by low-density array real-time PCR in 21 colorectal cancer cell lines, 14 xenografts and 25 tumors. Samples were grouped by unsupervised hierarchical clustering and the groups tested for associations with respective sensitivity, response and patient survival data. siRNA knockdown was performed to verify the influence of the top candidate on 5FU sensitivity in-vitro. 5FU sensitivity associated with clustered groups for xenografts and tumours, but not cell lines. CTPS2 and NME4 were the genes common to the significantly differentially regulated genes in xenografts and tumors. CTPS2 was also in the group of genes with the most distinct expression change following 5FU treatment in sensitive and resistant cell lines. Pathway-based analysis in multiple cancer models identifies CTPS2 expression as a major determinant of 5FU sensitivity.