期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：3
页码：839-844
DOI：10.1073/pnas.1423645112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe human EGF receptor (EGFR/HER) family plays critical roles in tumor progression. Therefore, several therapies intercepting these receptors were developed and clinically approved. Importantly, patients treated with such therapeutics often develop resistance, and in some cases this resistance has been associated with activation of HER3. Potentially, HER3 blockade might overcome patient resistance. Hence, antibodies to HER3 have been developed by us and other researchers. However, it has remained unclear which antibody attributes are required for effective tumor inhibition. To address this issue, we generated several monoclonal antibodies, which were tested in vitro and in tumor-bearing animals. Our results suggest that anti-HER3 antibodies able to intercept stroma-tumor interactions, as well as accelerate HER3 degradation, might inhibit tumor growth better than other antibodies. The human EGF receptor (HER/EGFR) family of receptor tyrosine kinases serves as a key target for cancer therapy. Specifically, EGFR and HER2 have been repeatedly targeted because of their genetic aberrations in tumors. The therapeutic potential of targeting HER3 has long been underestimated, due to relatively low expression in tumors and impaired kinase activity. Nevertheless, in addition to serving as a dimerization partner of EGFR and HER2, HER3 acts as a key player in tumor cells' ability to acquire resistance to cancer drugs. In this study, we generated several monoclonal antibodies to HER3. Comparisons of their ability to degrade HER3, decrease downstream signaling, and inhibit growth of cultured cells, as well as recruit immune effector cells, selected an antibody that later emerged as the most potent inhibitor of pancreatic cancer cells grown as tumors in animals. Our data predict that anti-HER3 antibodies able to intercept autocrine and stroma-tumor interactions might strongly inhibit tumor growth, in analogy to the mechanism of action of anti-EGFR antibodies routinely used now to treat colorectal cancer patients.
关键词：antibody combination ; cancer therapy ; HER3 ; signal transduction ; tyrosine kinase
