HER2 Pathway. Click to enlarge.
The first drug that successfully targeted the HER2 pathway in cancer treatment generated much excitement. In an unprecedented break from the typically sober language of scientific journals, the breast cancer drug Herceptin (trastuzumab) was touted as “a dramatic and perhaps permanent perturbation in the history of the disease, maybe even a cure” in a 2005 New England Journal of Medicine
commentary on pivotal trial results.
Since its approval in 1998, Herceptin, which targets the HER2 protein, has become one of the most common therapeutic agents used in the treatment of breast cancer. Now, researchers are seeking to build upon the drug’s success by exploring its potential in combination therapy, sharpening the methods of identifying HER2 overexpression, and developing biomarkers to better identify patients who would benefit from the therapy.
How the HER2 Pathway Functions
HER2 is a member of the human epidermal growth factor receptor (EGFR) 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.
Dimerization, the process through which two receptors such as HER2 join, plays a crucial role in receptor signaling. Multiple ligands bind to the different HER receptors with different binding specificity, exposing an extracellular dimerization domain and enabling 1 receptor molecule to pair with another.
The paired receptor molecules phosphorylate one another on tyrosine residues on their intracellular domains. The activated receptors are then able to bind to intracellular signaling molecules and initiate a variety of signaling pathways, including the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway.
HER2 has no known ligand, and therefore relies for activation on heterodimerization with other HER receptors, or homodimerization with itself when it is expressed at very high levels on the cell surface. The HER2 receptor remains in a constitutively active conformation. Consequently, HER2 is the preferred partner for other members of the HER family.
Herceptin may activate an immune response, leading to cell death.
HER2 Signaling and Cancer Explored
HER2-containing heterodimers are the most prevalent and active of all the receptor pair combinations. For this reason, the HER2 signaling pathway is a target of significant interest for cancer researchers. Since the discovery of the HER2/neu
oncogene in 1979, a high frequency and broad spectrum of aberrations in this pathway have been observed in human tumors.
Axel Ullrich, PhD, and H. Michael Shepard, PhD, researchers at the then-fledgling biotech company Genentech, identified the protein produced by this gene in 1984 and, together with Dennis Slamon, MD, PhD, discovered that the HER2 receptor is overexpressed in between 25% to 30% of breast cancers and is associated with more aggressive disease and a poorer outcome. More recent clinical data also support the role of HER2 in other tumor types, including gastric, thyroid, and head and neck cancers.
Defining the number of HER2 receptors remains controversial.
HER2-Targeted Therapies Take Shape
Interest in the HER2 pathway was stimulated, and in 1989, Ullrich and colleagues identified a monoclonal antibody that selectively bound to the extracellular domain of HER2, which specifically inhibited the growth of breast cancer cells overexpressing the HER2 receptor. This antibody was developed into the renowned drug trastuzumab (Herceptin, Genentech).
A wealth of clinical trials has demonstrated the efficacy of trastuzumab in combination with numerous chemotherapeutic agents. It became the first HER2-targeted therapy to gain FDA approval for the treatment of HER2-positive breast cancer. Landmark phase III trials reported in The New England Journal of Medicine
in 2005 demonstrated that trastuzumab given after primary therapy (including surgery and chemotherapy) reduced recurrence rates by approximately 50%.