Outcome of irinotecan and cetuximab treatment in colorectal cell lines. Correlation between signaling pathways, gene expression profile and cell cycle checkpoint.

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The recent successful development of novel monoclonal antibodies that target key components of biologic pathways has expanded treatment options for patients with colorectal cancer. Cetuximab is a recombinant chimeric epidermal growth factor receptor (EGFR) monoclonal antibody that was approved for use in combination with irinotecan in the treatment of EGFR-expressing, metastatic colorectal cancer. In this report, we investigated the cellular and molecular effects of cetuximab, in combination with chemotherapy in human CIN (chromosomal instability) HT29 colorectal cell line and in MIN (microsatellite instability) HCT116 colorectal cell line. HCT116 cells exhibit relatively more sensibility than HT29 cell to SN38 alone, the active metabolite of irinotecan, as determined by clonogenic assays. By contrast, cetuximab treatment increased the cytotoxic effect of SN38 in HT29 cells whereas its effects were relatively weak in HCT116 cells. The signaling pathways of EGFR receptor (PI3K, MAPK and STAT3), the gene expression profile (repair, apoptotic and cell growth controlling gene) and the treatment outcome (mitotic catastrophe, apoptosis, and senescence) explain the difference of sensibility observed between the two cell lines. These effects are related to a modulation of cell cycle progression as observed by multiparameter flow cytometry analysis. These results provide a best comprehension of molecular events that can predict the chemotherapeutic activity of SN38 and cetuximab. New chemotherapy strategies against resistant tumors may be envisaged from these results.