As resistance to current therapies remains one of the major hurdles to the successful treatment of advanced colorectal cancer, we need to understand the mechanisms by which cancer cells evade therapy-induced cell death. I have investigated whether there is a link between epithelial cell adhesions, and acquired resistance to 5-fluorouracil (5-FU). I compared three pairs of human colorectal 5-FU-sensitive and -resistant cell lines, and investigated whether there was a direct role for E-cadherin and/or the Src family kinase, c- Yes (which is co-amplified with thymidylate synthase) in promoting resistance to 5-FU. I found that while knockdown of c-Yes expression had no effect, disruption of E-cadherin using a blocking antibody caused a reduction in colon cancer cell proliferation and some re-sensitisation to 5-FU. The resistant cells displayed intrinsically higher activities of putative survival pathways, namely the PI3-kinase/Akt and the MEK/MAP kinase pathways, and these were suppressed when E-cadherin function was blocked. Furthermore, the resistant cells displayed a greater dependence on signalling via the PI3- kinase/Akt pathway for their survival. Finally, preliminary experiments established a possible link between the integrity of E-cadherin-mediated cell-cell junctions, signalling through the PI3-kinase/Akt pathway and nuclear localisation of the apoptotic regulatory tumour suppressor protein p53 in modulation of 5-FU-resistance.