ERBB3, also known as HER3, is a protein belonging to the epidermal growth factor receptor (EGFR/ERBB) family of receptor tyrosine kinases. This family of proteins relays signals from outside the cell to its interior, influencing cellular processes. As a cell surface protein, ERBB3 has an extracellular domain capable of binding specific ligands, molecules that can initiate a cellular response. This binding is fundamental for cellular communication and regulating cell behavior.
ERBB3’s Normal Biological Role
In healthy cells, ERBB3 functions as a receptor that helps regulate cell growth, differentiation, and survival. Unlike other ERBB family members, ERBB3 possesses a kinase-impaired domain, meaning it has very weak intrinsic enzymatic activity to phosphorylate other proteins. Instead, ERBB3 relies on forming partnerships, known as heterodimerization, with other ERBB family members to initiate signaling pathways.
Its primary partnership is with ERBB2 (also known as HER2), a receptor that lacks a direct ligand-binding domain but is the preferred dimerization partner for other ERBB receptors. When ERBB3 binds to its ligands, such as neuregulin-1 (NRG1) or NRG2, it undergoes a conformational change that promotes heterodimerization, particularly with ERBB2. This ERBB2-ERBB3 heterodimer becomes a potent signaling complex, activating downstream pathways like PI3K/Akt and MAPK, which are involved in cell proliferation and survival. The collaboration of ERBB2 and ERBB3 is important for processes like neuronal and heart development.
ERBB3 in Cancer Development
The normal function of ERBB3 can become dysregulated, contributing to the progression of various cancers. While ERBB3 overexpression or mutation alone may not be sufficient for oncogenesis, its role as a heterodimerization partner, especially with ERBB2, is implicated in promoting uncontrolled cell proliferation, survival, and metastasis. Aberrant ERBB3 signaling provides a growth advantage to cancer cells, influencing their ability to spread and resist therapies.
ERBB3 dysregulation is observed in several cancer types, including breast, lung, and colorectal cancers. In HER2-positive breast cancers, for instance, ERBB3 activation is a mechanism of resistance to HER2-targeted therapies. Similarly, in non-small cell lung cancer (NSCLC) with EGFR mutations, increased ERBB3 expression can lead to resistance to EGFR inhibitors by activating bypass signaling pathways. ERBB3 signaling, particularly through PI3K/Akt and MEK/MAPK pathways, promotes tumor metastasis and confers drug resistance.
Targeting ERBB3 in Therapy
Given its role in cancer progression and therapeutic resistance, ERBB3 has become a target for anti-cancer strategies. Since ERBB3 has weak intrinsic kinase activity, direct small molecule inhibitors are less common; instead, therapeutic approaches often focus on blocking its ability to bind ligands or form active heterodimers. Monoclonal antibodies are a primary strategy to inhibit ERBB3 activity.
These antibodies can work by blocking the binding of ligands like neuregulin to ERBB3, or by preventing ERBB3 from forming heterodimers with other ERBB family members, particularly ERBB2. The rationale behind targeting ERBB3, often in combination with other agents, is to overcome treatment resistance and enhance the effectiveness of existing therapies. This includes efforts to develop antibody-drug conjugates (ADCs) that deliver cytotoxic payloads directly to cancer cells expressing ERBB3, showing promising results in clinical studies for conditions like EGFR-TKI-resistant NSCLC.