Complex Signaling of the HER Gene Family
Click to enlarge.
The figure illustrates the HER family protein receptors at the cell surface and the various ways they initiate and influence cell signaling pathways.
Amp indicates amphiregulin; β-cel, β-cellulin; EGF, epidermal growth factor; Epi, epinephrine; HB-GF, heparin-binding growth factor; NRG, neuregulin; TGF%u0251, transforming growth factor %u0251; VEGF, vascular endothelial growth factor. Akt, MAPK, MEK, PI3K, RAF, RAS, and SOS denote signaling pathways.
Source: Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: ten years of targeted anti–HER-2 therapy and personalized medicine. The Oncologist. 2009;14:320-368. Reprinted with permission.
Since the discovery of the HER2/neu gene in the late 1970s, aberrations in the HER2 signaling pathway have been implicated in a wide variety of human cancers, most significantly in breast cancer. Substantial interest in this signaling pathway led to the development of the HER2-targeted drug trastuzumab (Herceptin, Genentech), which has become one of the most common therapeutic agents used in the treatment of breast cancer since its 1998 FDA approval.
Despite its successes, trastuzumab did not prove to be the “magic bullet” for cancer that many hoped it would be, and there are significant problems associated with resistance to therapy and cancer relapse. Recently, results presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium (SABCS) highlighted the exciting potential of an emerging therapeutic strategy involving a dual blockade of HER2 signaling with trastuzumab and a second HER2-targeted agent, pertuzumab. A new standard of care may be on the horizon for patients with HER2-positive breast cancer.
The Basics of HER2 Signaling
HER2 is a member of the human epidermal growth factor receptor family, along with 3 other proteins: HER1 or EGFR, HER3, and HER4, all of which are receptor tyrosine kinases that feed into a complex biological signaling network controlling numerous cellular processes, including proliferation, survival, differentiation, angiogenesis, invasion, and metastasis.
Receptor dimerization, a process through which 2 receptors such as HER2 receptors join, is an essential requirement for HER function and for the signaling activity of all HER receptors. Dimerization can occur between 2 different HER receptors (heterodimerization) or between 2 molecules of the same receptor (homodimerization).
Not all HER dimers have equivalent signaling potency. For example, homodimers are generally weaker than heterodimers. Heterodimers of HER2 and HER3 molecules have been shown to be particularly potent and are critical for the activation of the phosphatidylinositol-3-kinase (PI3K)/Aktmammalian target of rapamycin (mTOR) pathway, an important downstream signaling pathway that drives angiogenesis, cell survival, migration, apoptosis, and proliferation.
HER receptors normally exist as inactive monomers, with the molecules folded in a way that prevents dimerization, and only become active upon binding of their respective ligands. HER2, on the other hand, has no known ligand and remains in a constitutively active formation. HER2 activation is achieved through either homodimerization with other HER2 molecules (ligand-independent activation) or through heterodimerization with other ligand-activated HER receptors (ligand-dependent activation).
In many types of human cancer, the HER2 gene is amplified and/or HER2 is overexpressed at the mRNA or protein level. This occurs in about 20% of patients with early-stage breast cancer and in a number of other tumor types including gastric, thyroid, and head and neck cancers. Clinically, HER2-overexpressing breast tumors have historically been associated with a more aggressive phenotype and poorer outcomes.
Trastuzumab: The First HER2-Targeted Therapy
In 1989, researchers at Genentech identified the first HER2- targeted therapy, a monoclonal antibody that specifically binds to the extracellular domain of the HER2 receptor and inhibits the growth of HER2-overexpressing breast cancer cells.
The antibody was developed into the renowned drug Herceptin, and in phase III trials, trastuzumab given after primary therapy (including surgery and chemotherapy) was shown to reduce recurrence rates by approximately 50% in patients with HER2-positive breast cancer.
The FDA has subsequently approved trastuzumab for the treatment of HER2-positive early-stage breast cancer and metastatic breast cancer, either as monotherapy or in combination with the chemotherapy drug paclitaxel. It is also approved for the treatment of metastatic HER2-positive stomach or gastroesophageal cancer in combination with a chemotherapy regimen (cisplatin and either capecitabine or 5-fluorouracil).