Anti-EGFR and ErbB-2 antibodies attenuate cyclooxygenase-2 expression and cooperatively inhibit survival of human colon cancer cells.

Cyclooxygenase-2 (COX-2) is a transcriptional target and downstream effector of the ErbB-1 (EGFR) and ErbB-2 signaling pathways. We found that anti-EGFR and anti-ErbB-2 antibodies inhibited ERK phosphorylation and downregulated COX-2 protein expression in HCA-7 human colon carcinoma cells. Both antibodies also augmented the cytotoxic effects of the selective COX-2 inhibitor, NS-398. Inhibition of EGFR and ErbB-2 attenuated cell growth by increasing cell death, and the antibody combination suppressed cell growth to a greater extent than did either antibody alone. In conclusion, EGFR and ErbB-2 regulate ERK-mediated COX-2 expression and their selective inhibition enhanced NS-398-induced cell death. Cooperative inhibition of cell growth by EGFR and ErbB-2 blockade suggests the therapeutic potential of targeting multiple ErbB receptors.