HER3, or human epidermal growth factor receptor 3, is a protein located on the outer membrane of various cells throughout the body. It functions as a receiver, playing a part in the intricate network of cell communication. This protein helps cells interpret signals from their environment, which guides their behavior and development. HER3 supports normal cell growth, division, and survival, maintaining cellular balance.
Understanding the HER Family and HER3’s Function
HER3 is one of four related proteins, including HER1 (also known as EGFR), HER2, and HER4, that together form the HER family of receptor tyrosine kinases. These proteins normally operate by forming pairs, a process called dimerization, which allows them to transmit signals from outside the cell to its interior. When a specific signaling molecule, or ligand, binds to a HER family member, it can induce a change in the receptor’s structure, enabling it to pair with another HER protein. This dimerization then activates internal signaling pathways within the cell.
HER3 has an impaired ability to directly activate its own internal signaling machinery. It cannot effectively signal on its own, relying on partnerships with other HER family members to become fully active. It frequently forms heterodimers, particularly with HER2, which then allows for the activation of downstream pathways. This partnership is how HER3 contributes to regulating normal cell growth, survival, and development, ensuring cells respond appropriately to external cues.
How HER3 Contributes to Cancer Growth
In cancer, HER3’s normal function can become altered, contributing to uncontrolled cell growth and tumor progression. Overexpression of HER3, where too many proteins are present on cancer cell surfaces, is a common mechanism. This increases the likelihood of HER3 forming active partnerships, particularly with HER2, amplifying signaling within the cell. Such increased dimerization drives cancer cell proliferation and survival.
Once activated, HER3 engages pro-growth pathways inside cancer cells, notably the PI3K/Akt pathway. HER3’s intracellular tail contains multiple sites that, when phosphorylated, can directly recruit and activate components of this pathway. The PI3K/Akt pathway drives cell growth, survival, and resistance to programmed cell death, making its sustained activation by HER3 a factor in tumor development. This dysregulated HER3 activity is implicated in various cancers, including breast, lung, and colorectal cancers, where it promotes tumor growth, helps cancer cells evade destruction, and can contribute to the spread of the disease to other parts of the body.
Developing Therapies Against HER3
Strategies are being developed to target HER3 in cancer treatment, aiming to counteract its pro-cancerous activities. One approach uses monoclonal antibodies designed to specifically bind to HER3 on the cell surface. By binding to HER3, these antibodies can block its ability to interact with its signaling partners or prevent ligands from attaching, thereby inhibiting the formation of active HER3 dimers and shutting down downstream pro-growth signals.
Another strategy involves antibody-drug conjugates (ADCs), combining an antibody’s precise targeting with a potent, cell-killing drug. The antibody component specifically recognizes and attaches to HER3-expressing cancer cells, acting like a guided missile. Once bound, the ADC is internalized by the cancer cell, releasing its toxic payload directly inside, leading to cancer cell death while minimizing harm to healthy tissues. The overarching goals of these HER3-targeted therapies are to halt tumor growth, induce cancer cell death, and potentially overcome mechanisms of resistance that tumors develop against other treatments.
Addressing Treatment Resistance in HER3-Targeted Therapies
Cancer cells can develop mechanisms to bypass or become resistant to HER3-targeted therapies over time. Resistance can emerge through activation of alternative signaling pathways that compensate for the blocked HER3 pathway. Cancer cells may also acquire new genetic mutations that alter the HER3 protein itself or other components of the signaling network, allowing them to escape the effects of the therapy.
Researchers are developing new generations of drugs to more effectively inhibit HER3 signaling or target alternative pathways. Combination therapies are also being explored, where HER3-targeted agents are administered alongside drugs that target other pathways simultaneously. This multi-pronged approach aims to block multiple survival routes for cancer cells, leading to a more comprehensive and lasting therapeutic response for patients.