The human epidermal growth factor receptor (HER) family plays an important role 
in cell survival and proliferation, and is implicated in oncogenesis. 
Overexpression of HER2 is associated with aggressive disease and poor prognosis. 
Trastuzumab is a humanized monoclonal antibody targeting HER2 and has proven 
survival benefit for women with HER2-positive early and metastatic breast 
cancer. Pertuzumab, another monoclonal antibody, is a HER2 dimerization 
inhibitor that binds to a different epitope on HER2 than trastuzumab and 
inhibits HER2 dimer formation with other HER family members such as HER3 and 
HER1. We investigated the antitumor activity of these agents alone and in 
combination in HER2-positive breast and non-small cell lung cancer xenografts. 
Our data show that the combination of trastuzumab and pertuzumab has a strongly 
enhanced antitumor effect and induces tumor regression in both xenograft models, 
something that cannot be achieved by either monotherapy. The enhanced efficacy 
of the combination was also observed after tumor progression during trastuzumab 
monotherapy. Near-IR fluorescence imaging experiments confirm that pertuzumab 
binding to tumors is not impaired by trastuzumab pretreatment. Furthermore, we 
show by in vitro assay that both trastuzumab and pertuzumab potently activate 
antibody-dependent cellular cytotoxicity. However, our data suggest that the 
strongly enhanced antitumor activity is mainly due to the differing but 
complementary mechanisms of action of trastuzumab and pertuzumab, namely 
inhibition of HER2 dimerization and prevention of p95HER2 formation.