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

Abstract

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 and death. These articles, together with one from the Nusse 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, and other cancer types have 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 therapies will also be mentioned and some reflections on the future of ErbB2 targeting will end the commentary.The ErbB Receptor-Ligand Network EGFR, ErbB2, as well as ErbB3 and ErbB4, which were discovered using homology cloning a few years after ErbB2, make up the subtype 1 of the receptor tyrosine kinase (RTK) family. Like other members of this superfamily, ErbBs are regulated by ligand binding. In 1962, Cohen isolated the first ligand, EGF, well before its receptor was cloned. With the exception of TGFa, which was discovered by Sporn and Roberts in 1982, the other five EGFR ligands, as well as the neuregulins/heregulins, which bind ErbB3 and ErbB4, were discovered after ErbB2. All ligands have a characteristic pattern of six conserved cysteine residues forming three intramolecular disulfides, so-called EGF-like domains (reviewed in refs. 6, 7). Ligand binding to the ectodomain stabilizes receptor dimers and leads to activation of their intracellular kinase domain....

Mechanism of Allosteric Coupling into and through the Plasma Membrane by EGFR

“…Over a quarter of breast cancers are characterized by ErbB2 overexpression (Hynes, 2016; Slamon et al, 1987), and ErbB2 is the only ErbB family member that does not require a growth factor to stimulate receptor homo- and hetero-dimerization and kinase activation. ErbB2 and EGFR share a high level of sequence identity within the JM segment – 68% overall and 75% within the 12-residue helix-forming JM-A region (660 to 671 in ErbB2; residues 652 to 663 in EGFR) (Figure 7A).…”

Teneurins: An Integrative Molecular, Functional, and Biomedical Overview of Their Role in Cancer

“…Interestingly, ERBB4 expression increased over 5-fold upon ZEB1 knockout, with a concomitant 16-fold increase in Tenerin-2, which agrees with the association proposed for these gene families. In the case of breast cancer, it is interesting to speculate that the positive prognostic impact of Teneurin-1 overexpression (Table 2) might be associated with a simultaneous expression of ERBB receptors, which provide an actionable target for directed therapies able to positively impact on patient survival (Hynes, 2016). This interaction illustrates how additional factors can modify an expected prognostic impact predicted by molecular parameters.…”

Molecularly targeted therapies in cancer: a guide for the nuclear medicine physician

“…Trastuzumab is a monoclonal antibody given intravenously that interferes with the HER2/neu receptor, and is well known for its activity in ErbB2-positive breast cancer [ 49 , 50 ]. Another HER2 antibody (pertuzumab) was also approved for use in combination with trastuzumab and docetaxel for neoadjuvant treatment of ErbB2-positive breast cancer patients [ 51 ]. Lapatinib is the first dual inhibitor in clinical use acting as a tyrosine kinase inhibitor of EGFR and HER2 used in the treatment of ErbB2-overexpressing breast cancer [ 52 ].…”