Interleukin-2 potentiation of cetuximab antitumor activity for epidermal growth factor receptor-overexpressing gastric cancer xenografts through antibody-dependent cellular cytotoxicity

Cetuximab, a chimeric monoclonal antibody to epidermal growth factor receptor (EGFR), has been proved to have clinically significant antitumor activity against advanced colorectal cancers, but its therapeutic activity for gastric cancers remains unclear. In the present study, we investigated the antitumor effect and action mechanism of cetuximab using EGFR high-expressing (MKN-28) and EGFR low-expressing (GLM-1) gastric cancer cell lines without gene amplification. Cetuximab showed neither significant growth inhibition nor induction of apoptosis in either cell line in vitro, and only slightly inhibited ligand-induced phosphorylation of protein kinase B and extracellular signal-regulated kinase in MKN-28 cells. In contrast, cetuximab significantly inhibited subcutaneous and intraperitoneal tumor growth of MKN-28 cells, but not GLM-1 cells, in nude mice. This antitumor activity was significantly enhanced and diminished in nude mice by treatment with interleukin-2 (IL-2) and antiasialo GM1 antibody, which can expand and deplete natural killer (NK) cells, respectively. Antibody-dependent cellular cytotoxicity (ADCC) of cetuximab, as measured by Cr-51 release assay, was significantly higher in MKN-28 than in GLM-1 cells. This ADCC activity was enhanced by IL-2 and reduced by heat-aggregate of human immunoglobulin G, an inhibitor for FcR-III of NK cells. These results suggest that cetuximab in combination with IL-2 shows significant antitumor activity against EGFR high-expressing gastric cancer mainly through NK cell-mediated ADCC. Combination therapy with cetuximab and IL-2 would thus offer a new potential therapeutic approach for a subset of EGFR-overexpressing gastric cancers.