HER3, or Human Epidermal Growth Factor Receptor 3, is a protein found on the surface of many cells. This protein functions like an antenna, constantly scanning the extracellular environment for specific molecular signals. Upon receiving a signal, HER3 initiates a cascade of communication within the cell. This internal signaling network regulates fundamental cellular processes, primarily instructing the cell to grow, divide, and survive.
The HER Receptor Family and HER3’s Unique Role
HER3 is one of four members belonging to the Epidermal Growth Factor Receptor (EGFR) family, also known as the ErbB family, which includes HER1, HER2, and HER4. These receptors are receptor tyrosine kinases, which typically activate signaling by adding phosphate groups to other proteins inside the cell. HER3 is unique because its intracellular domain possesses only weak or nearly non-existent intrinsic tyrosine kinase activity.
Because of this functional impairment, HER3 cannot effectively signal on its own, rendering it a “pseudokinase.” It must partner with one of the other three active HER family members to transmit growth signals. This partnering process, known as dimerization, is how HER3 receives the necessary activating phosphate groups. The most potent partner for HER3 is HER2, which is an effective dimerization partner. The resulting HER2:HER3 heterodimer is a powerful signaling unit.
Driving Tumor Growth and Therapy Resistance
Abnormal activation or overexpression of HER3 is a significant factor in the development and progression of various cancers, including those of the breast, lung, and colon. When HER3 is highly expressed, it forms numerous heterodimers, especially with HER2, leading to increased pro-growth signaling. This activated dimerization complex strongly engages the PI3K/Akt pathway, a key survival pathway within the cell.
HER3 is uniquely equipped to activate this pathway because its intracellular tail contains six specific binding sites for the p85 regulatory subunit of PI3K. Sustained activation of the PI3K/Akt pathway promotes uncontrolled cell proliferation and shields the cell from programmed death signals. This persistent survival signaling is a primary mechanism by which tumors maintain rapid growth.
HER3 often acts as a bypass mechanism, allowing cancer cells to survive when other growth pathways are blocked by therapy. For instance, when tumors are treated with inhibitors targeting HER2 or EGFR, the cancer cell compensates by upregulating HER3 activity. The HER3 protein partners with remaining active receptors to reactivate the PI3K/Akt pathway, maintaining cell growth despite treatment. This compensatory activation is a common cause of acquired drug resistance and disease relapse.
Clinical Assessment of HER3
Determining the status of HER3 in a patient’s tumor is important because its expression level influences both prognosis and treatment selection. Pathologists use various methods to assess if HER3 is present and active in the tumor tissue. One common technique is Immunohistochemistry (IHC), which uses specific antibodies to detect and quantify the amount of HER3 protein expressed on the cell surface.
Genetic sequencing may also be performed to check for specific mutations within the ERBB3 gene, which codes for the HER3 protein. High levels of HER3 expression or activating mutations are associated with a more aggressive disease course and a poorer prognosis. Identifying these molecular characteristics helps oncologists select patients who may benefit most from therapeutic agents that specifically target the HER3 pathway.
Strategies for Targeting HER3 in Treatment
Developing drugs that effectively target HER3 is challenging due to its unique role as a pseudokinase that relies on partners for activation. Researchers have developed several distinct classes of therapeutic agents designed to interfere with HER3 signaling.
Monoclonal Antibodies (mAbs)
One established approach uses Monoclonal Antibodies (mAbs), which are large proteins designed to physically block the HER3 receptor. These antibodies bind to the extracellular domain of HER3, preventing its natural ligand from attaching and inhibiting its ability to dimerize with other HER family members like HER2. Blocking the dimerization interface effectively shuts down the formation of the highly active HER2:HER3 signaling complex.
Antibody-Drug Conjugates (ADCs)
A contemporary strategy involves Antibody-Drug Conjugates (ADCs), a sophisticated form of targeted chemotherapy. An ADC consists of three parts: a monoclonal antibody that binds specifically to HER3, a potent chemotherapy payload, and a linker connecting the two. Once the antibody binds, the complex is internalized by the cell. The linker is then cleaved, releasing the toxic chemotherapy directly into the cancer cell, which minimizes systemic exposure and reduces damage to healthy tissues.
Small Molecule Inhibitors
Small molecule kinase inhibitors are also being explored, though the lack of strong intrinsic HER3 kinase activity complicates their design. Instead of directly blocking HER3’s internal kinase domain, these small molecules often block downstream signaling components, such as the PI3K/Akt pathway, that are activated by HER3 dimerization. These inhibitors aim to interrupt the survival signals initiated by HER3, regardless of the activating partner.