The ERBB family consists of four related proteins that function as receptor tyrosine kinases (RTKs). These proteins are located on the surface of cells and play an important role in how cells communicate and respond to their environment. RTKs are a class of cell surface receptors that bind to specific signaling molecules, primarily growth factors, to transmit signals into the cell. This signaling is crucial for regulating cellular activities, including how cells grow, divide, move, and survive. The ERBB family’s involvement in these processes highlights their significance in maintaining normal tissue function and development. Their ability to control such a wide array of cellular behaviors makes them a focal point in understanding both healthy biological systems and the progression of various diseases.
The ERBB Family Members and Their Roles
The ERBB family consists of four members: ERBB1, ERBB2, ERBB3, and ERBB4. ERBB1 is also known as the Epidermal Growth Factor Receptor (EGFR or HER1), ERBB2 as HER2, ERBB3 as HER3, and ERBB4 as HER4. Each has an extracellular part that binds to signaling molecules, a segment that spans the cell membrane, and an intracellular part with tyrosine kinase activity.
When a growth factor binds to the extracellular domain of an ERBB receptor, it causes two receptor molecules to come together, or “dimerize.” This dimerization activates the tyrosine kinase domain, which then adds phosphate groups to specific tyrosine residues on the receptor and other proteins. This process, called autophosphorylation, initiates a cascade of signals inside the cell, influencing cell proliferation, differentiation, migration, and survival.
Each ERBB family member has unique characteristics that contribute to their diverse roles. ERBB1 (EGFR) is activated by several ligands, including epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α), and plays a role in cell proliferation, differentiation, migration, and survival. ERBB2 (HER2) is unique because it does not directly bind a ligand but is activated by forming heterodimers with other ligand-bound ERBB family members. ERBB3 (HER3) has an impaired kinase domain, meaning it has very low intrinsic kinase activity, and primarily signals by forming heterodimers, especially with ERBB2, to activate downstream pathways like the PI3K/AKT pathway. ERBB4 (HER4) binds to ligands such as neuregulins and can participate in various processes including cell division, differentiation, and even has growth-inhibiting properties in some contexts.
When ERBB Proteins Go Wrong
Dysregulation of ERBB proteins can lead to cancer. One common mechanism of dysregulation is gene amplification, where extra copies of an ERBB gene are present, leading to an excessive amount of the protein on the cell surface. For instance, HER2 gene amplification occurs in approximately 15% to 20% of invasive breast cancers, resulting in HER2 protein overexpression. This overexpression drives uncontrolled cell proliferation and survival, contributing to an aggressive tumor phenotype.
Mutations in ERBB genes also contribute to cancer. For example, specific mutations in the EGFR gene are frequently found in non-small cell lung cancer (NSCLC) and are also observed in colorectal cancer. These mutations can lead to constitutive activation of the receptor, meaning it is continuously active even without a ligand binding, which promotes uncontrolled cell growth and tumor progression. Overexpression of ERBB proteins, whether due to gene amplification or other mechanisms, can enhance tumor cell motility and invasiveness, facilitating metastasis.
The aberrant activation of ERBB signaling pathways, such as the RAS/MAPK and PI3K/AKT pathways, is a common feature in many solid tumors. This continuous signaling promotes cell proliferation, inhibits programmed cell death (apoptosis), and contributes to drug resistance. These altered proteins drive the uncontrolled cell division and survival characteristic of tumor growth and progression.
Targeting ERBB in Disease Treatment
Understanding ERBB dysregulation has led to the development of targeted therapies that interfere with their aberrant activity. These therapies aim to block the signals that drive uncontrolled cell growth, offering a more precise approach than traditional chemotherapy. Two main classes of drugs are utilized: monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs).
Monoclonal antibodies, such as Trastuzumab (Herceptin) and Cetuximab (Erbitux), are designed to bind to the extracellular domain of ERBB receptors. Trastuzumab specifically targets HER2, approved for HER2-positive breast and gastric cancer, by binding to the receptor to prevent activation and inhibit tumor cell growth. Cetuximab targets EGFR (ERBB1) for metastatic colorectal and head and neck cancer, blocking growth factor binding to inhibit receptor activation and downstream signaling. These antibodies can also induce the internalization and degradation of the receptors, further reducing their signaling.
Small molecule tyrosine kinase inhibitors (TKIs) like Gefitinib (Iressa) and Erlotinib (Tarceva) are designed to block the intracellular kinase activity of ERBB receptors. These drugs are small enough to enter the cell and compete with ATP for binding to the kinase domain, preventing the receptor from phosphorylating itself and other proteins. Gefitinib and Erlotinib primarily target EGFR and are used in treating non-small cell lung cancer with activating EGFR mutations. Other TKIs, such as Lapatinib, Neratinib, Tucatinib, and Pyrotinib, target HER2 or both EGFR and HER2, and are approved for breast cancer treatment. These targeted therapies have improved patient outcomes by slowing tumor progression and increasing survival in patients with ERBB-driven cancers.