ErbB2: From an EGFR Relative to a Central Target for Cancer Therapy.

See related article by Berger et al., Cancer Res 1988;48:1238–43. Shortly after the discovery of the ErbB2/HER2–encoding gene, identified in the mid-1980s based on homology with the avian viral oncogene v-ErbB/EGFR (reviewed in ref. 1), publications describing ERBB2 amplification in a significant proportion of breast tumors appeared (2, 3). Indeed, ERBB2 amplification was the first consistent genetic alteration discovered in breast cancer. Moreover, data supporting the clinical relevance of ErbB2 were presented in these articles; patients with the chromosome 17q12-21 ERBB2 amplicon had dramatically elevated levels of the receptor, which was associated with an increased risk of early relapse anddeath. These articles, together withone from theNusse laboratory showing that a high percentage of ductal carcinoma in situ had ErbB2 overexpression (4), paved the way for development of anticancer agents targeting ErbB2. Since then, a wealth of clinical data implicating ErbB2, not only in breast, but also in gastric, ovarian, endometrial, colorectal, andother cancer typeshave been published. Importantly, based on these first studies in breast cancer, ErbB2 was considered to be an excellent therapeutic target. Many laboratories in academia and in pharmaceutical companies contributed to developing ErbB2 inhibitors. Currently, there are four FDA-approved therapeutics targeting ErbB2: the humanized antibodies trastuzumab, and pertuzumab, the kinase inhibitor lapatinib, and trastuzumab–emtansine, an antibody–microtubule polymerization inhibitor conjugate (reviewed in ref. 5). The field of ErbB2 biology has exploded in the almost 30 years since the publications describing ErbB2 overexpression in breast cancer. In this short commentary, it is impossible to discuss all the important and exciting articles that have appeared during this period. I decided to discuss work that contributed to deciphering the role of ErbB2 signaling in cancer and in normal physiology, as well as important structural studies on the ErbB receptors. The clinical success of ErbB2-targeted therapieswill also bementioned and some reflections on the future of ErbB2 targeting will end the commentary.