The endeavor to develop human epidermal growth factor receptor 2 (HER2)–targeting agents for cancer therapy now spans more than two decades, with four drugs already on the market and numerous others in the pharmaceutical pipelines. The interest in this mode of cancer therapy continues to intensify, particularly in the era of personalized medicine, because HER2 amplification underlies the biology of subsets of a large variety of cancers, including breast, gastric, esophageal, endometrial, ovarian, colorectal, bladder, head and neck, and others.

HER2 is a receptor tyrosine kinase located at the cell membrane with a large extracellular domain (ECD) and an intracellular catalytic kinase domain (KD) and signaling tail. Signal generation by HER2 occurs through heterodimerization with its HER family siblings (epidermal growth factor receptor, HER3, HER4), particularly HER3 (Fig 1). This process is prompted by ligand binding to HER3, which reconfigures its ECD exposing the interface that mediates dimerization with HER2. The proximation leads to the allosteric activation of the HER2 KD by the HER3 KD. The activated HER2 KD then phosphorylates the c-tail of HER3, leading to recruitment of several proteins and initiating a series of parallel signaling cascades that ultimately execute the phenotypic changes in cell behavior. Numerous cell cultured and mouse transgenic models have confirmed that the overexpression of HER2 is tumorigenic and continues to be a driver of the tumors that it generates. 1, 2 It is now also apparent from several cell-based, xenograft, and transgenic mouse models that HER3 is an essential partner and codriver for HER2 in tumorigenesis. 3-5 HER3 functions both upstream and downstream of HER2. It functions upstream because its own KD, although catalytically inactive, is a highly competent allosteric activator of the HER2 KD. 6 It functions downstream because it is a key substrate of HER2, particularly competent at recruiting and activating PI3K, and HER2 activates this pathway through the phosphorylation of the HER3 c-tail. 7, 8 The 25-year endeavor to develop targeted therapies for this type of cancer has had an evolutionary course closely following the trail of scientific developments. The monoclonal antibody trastuzumab was developed in the early days following the discovery of HER2 and is now known to bind the juxta-membrane region of the HER2 ECD. 9, 10 Pertuzumab was designed much later to interfere with HER2 signaling and binds the dimerization interface of the HER2 ECD (Fig 1). 11, 12 These agents exhibit only limited activity in the monotherapy of advanced-stage HER2-amplified breast or gastric cancers. 13-17 But they do enhance the efficacies of active chemotherapy regimens and have become staples of combination regimens for the management of