Abstract
Human epidermal growth factor receptor 2 (HER2)-targeted therapy by trastuzumab has become increasingly important for treating HER2-positive cancers, and trastuzumab emtansine (T-DM1) is expected to serve as an effective alternative to trastuzumab. Pertuzumab, a HER2 dimerization inhibitor, showed prolonged progression-free survival when used with trastuzumab for HER2-positive breast cancer. In this study, we investigated the effect of combining T-DM1 and pertuzumab on xenografted gastric tumors. T-DM1 as a single agent showed significant antitumor activity in all the three HER2-high expression tumor models tested (NCI-N87, SCH and 4-1ST) but was ineffective against two HER2-low expression tumors (SNU-16 and MKN-28). Using the T-DM1-sensitive NCI-N87 model, the combination efficacy of T-DM1 and pertuzumab was elucidated. The combination induced significant tumor regression, whereas T-DM1 or pertuzumab alone did not. In cultured NCI-N87 cells stimulated with epidermal growth factor (EGF) or heregulin-α, concomitant treatment of T-DM1 and pertuzumab significantly inhibited proliferation and increased caspase 3/7 activity compared to either agent alone. Only the combination significantly inhibited the phosphorylation of EGFR or HER3, and its downstream factor AKT. Suppressed HER3 phosphorylation by the combination was also seen in the NCI-N87 xenografted tumors. Compared to single agent treatments, the combination treatment significantly enhanced antibody-dependent cellular cytotoxicity (ADCC) against NCI-N87 cells. These findings suggest that T-DM1 in combination with pertuzumab shows significant antitumor activity by increasing AKT signal inhibition and ADCC in HER2-positive gastric cancers.