HER2 (human epidermal growth factor receptor 2) is a 185-kDa transmembrane receptor in the HER family of receptor tyrosine kinases, which also includes HER1, HER3 and HER4. Each of these receptors consists of an extracellular binding domain, a transmembrane lipophilic segment, and (except for HER3) a functional intracellular tyrosine kinase domain. The tyrosine kinase domains are activated by both homodimerization and heterodimerization, generally induced by specific ligands. Unlike the extracellular domains of the three other HER receptors, that of HER2 can adopt a fixed conformation resembling a ligand-activated state, permitting it to dimerize in the absence of a ligand and, once activated, able to induce signaling that promotes proliferation and survival.
1) HER2 overexpression is relevant but not sufficient to induce transformation. Indeed, in mouse models, transgenic expression of the rat proto-oncogene HER2 induced tumors only when accompanied by alterations such as deletions in the sequence of the oncoprotein. Furthermore, crossbreeding with mice transgenically expressing other cancer-related alterations was required to induce tumors. p53 status greatly influences the final effect of HER2 overexpression in tumor cells in promoting proliferation versus apoptosis and a block in proliferation. Indeed, HER2 overexpression was found to be associated with proliferation when induced in tumor cells with mutated p53, whereas HER2-transfected cells bearing wild-type p53 became apoptotic shortly after transfection, and after stabilization of apoptosis-resistant cells, showed decreased proliferation.
2) Women with HER2-positive tumors have a poorer prognosis than those with HER2-negative tumors. It was found that HER2 3+ cases were expected to was associated with poor prognosis, even in node-negative patients. The biological characteristics of HER2 3+ tumors probably reflect the amplification of HER2 as a driving event that conditions other pathological and biological features, such as high vascular invasion and high proliferation rates. Nevertheless, the prognostic value of HER2 is related only to the first 3 -- 4 years after surgery due to events occurring at the time of surgery.
3) HER2 overexpression has been implicated as a potential indicator of responsiveness to some chemocal drugs, such as cyclophosphamide, methotrexate and fluorouracil (CMF) treatment, and doxorubicin.
4) HER2 overexpression has been reported to identify a subset of tumors characterized by: the lack of expression of genes associated with hormone receptor signaling pathways; high-level expression of a cluster of genes associated with proliferation; and the presence of undifferentiated stem cells. These findings suggest a pattern of gene expression peculiar to HER2-expressing tumors and raise the possibility that all of the clinical features thus far associated with HER2.
Two major types of receptor inhibitors have been developed for therapy: i) humanized monoclonal antibodies directed against the HER2 extracellular domain; and ii) small-molecule tyrosine kinase inhibitors, which compete with ATP in the kinase domain of this receptor to impair the transmission of proliferation signal.
Trastuzumab was humanized at Genentech by inserting the complementarity-determining regions of a monoclonal antibody into the human immunoglobulin G1 framework. The inserted monoclonal antibody recognizes an epitope in the cysteine-rich II domain of the
extracellular portion. Trastuzumab binds to the extracellular domain IV of HER2, which results in the down-regulation of the PI3K/Akt pathway. Trastuzumab has different mechanisms of action, including antibody-dependent cell-mediated cytotoxicity (ADCC), prevention of HER2 extracellular domain shedding, and angiogenesis inhibition; however, inhibition of signaling transduction is thought to be its main mechanism of action. Because of the survival benefit, trastuzumab was approved in 1998 by the FDA for clinical treatment of women with HER2-positive metastatic breast carcinomas.
Pertuzumab is a fully humanized monoclonal antibody which binds to domain II of HER2, essential for dimerization. Pertuzumab inhibits the formation of both heterodimers and homodimers in the presence of an HER2 ligand; more specifically, it inhibits the potent HER2–HER3 interaction in the presence of heregulin (HRG), which activates the PI3k/Akt signaling pathway. Like trastuzumab, it also induces ADCC as one of its major mechanisms of action .
Lapatinib is a dual TKI of both HER1 and HER2 and the most advanced in clinical development, blocks tumor
cell proliferation by inhibiting phosphorylation of the receptors and preventing downstream signal transduction of
PI3K and Ras. Analysis of lapatinib activity on a large panel of breast cancer cell lines expressing various levels of HER1
(EGFR) and HER2 indicated a direct relationship of drug sensitivity only to HER2. Lapatinib has also been
reported to have activity against trastuzumab-resistant cells and, in combination with trastuzumab, to synergize in enhancing apoptosis in HER2-overexpressing cell lines.
The benefit of anti-HER2 therapies demonstrated in clinical trials indicates that HER2 is, to date, one of the most promising molecules for targeted therapy. Nevertheless, since tumor cells utilizing alternative growth signaling pathways through transmembrane receptors as well as intracellular signaling transduction molecules can bypass HER2 blockade, a future ambitious aim is the successful combination of anti-HER2 strategies with drugs directed to molecules that contribute to anti-HER2 resistance.
• Tagliabue E, et al. HER2 as a target for breast cancer therapy[J]. Expert opinion on biological therapy, 2010, 10(5): 711-724.
• Capelan M, et al. Pertuzumab: new hope for patients with HER2-positive breast cancer[J]. Annals of oncology, 2012: mds328.