In recent years, the receptor tyrosine kinase HER3 (also known as ErbB3) has emerged from relative obscurity to occupy a central role in cancer biology and therapeutic development. Part of the broader HER/ErbB family, which includes EGFR (HER1), HER2, and HER4, HER3 has long been recognized for its unusual biochemical properties. Unlike its family members that possess robust intrinsic kinase activity, HER3’s kinase function is weak, almost vestigial. For many years, this led to the assumption that HER3 played a secondary or auxiliary role in cellular signalling. However, mounting evidence now illustrates how HER3’s unique characteristics contribute profoundly to oncogenic signalling networks, impact tumor progression, and importantly, present novel therapeutic avenues that can be harnessed to treat previously refractory cancers.
HER3 functions predominantly through ligand-induced heterodimerization with other HER receptors, especially HER2, forming complex receptor pairs that initiate downstream signalling cascades critical for cell proliferation, survival, and differentiation. The high-affinity ligand for HER3, neuregulin 1 (NRG1), triggers this dimerization, enhancing HER3’s ability to drive oncogenic pathways. This mechanism allows HER3 to exert a potent influence on tumor cell biology despite its weak intrinsic kinase capacity. Clinically, aberrant expression or alterations in HER3 have been detected across an array of malignancies — including lung, pancreatic, breast, and colorectal cancers — with several studies correlating elevated HER3 activity to poor patient outcomes and therapy resistance. As such, understanding the nuances of HER3 signalling has become a critical focus, promising new insights into cancer pathogenesis and therapeutic resistance mechanisms.
Targeting HER family receptors is a cornerstone of precision oncology. For decades, drugs inhibiting EGFR and HER2 have delivered significant clinical benefits in cancers such as non-small-cell lung cancer (NSCLC) and breast cancer, fundamentally transforming treatment paradigms. Yet, despite the clear oncogenic role of HER3, clinical targeting of this receptor proved elusive. Early attempts relied on monoclonal antibodies designed to block HER3’s ligand binding or dimerization capabilities. Disappointingly, these efforts, whether as monotherapy or combined with other agents, failed to produce substantial or durable responses in clinical trials. The underlying biological complexities, including HER3’s kinase deficiency and its reliance on heterodimerization, contributed to these setbacks, highlighting the need for innovative strategies capable of effectively intercepting HER3-driven signalling.
In recent years, the development of next-generation therapeutic agents has reinvigorated the pursuit of HER3 as a viable target. Among the most notable are antibody–drug conjugates (ADCs), which harness the specificity of antibodies to deliver potent cytotoxic agents directly to HER3-expressing cancer cells, thereby maximizing efficacy and minimizing off-target toxicity. Additionally, bispecific antibodies engineered to simultaneously engage HER3 and HER2 have emerged as promising modalities. These bispecific constructs can disrupt HER3/HER2 heterodimerization and activate immune-mediated cytotoxicity, offering a dual mechanism of antitumor activity. Early-phase clinical trials have demonstrated encouraging activity of these agents across multiple tumour types, suggesting that HER3-directed therapies are finally poised to enter mainstream oncology practice.
December 2024 marked a pivotal milestone with the FDA’s accelerated approval of zenocutuzumab, the first HER3 × HER2 bispecific antibody approved for clinical use. This approval specifically targets patients with NSCLC or pancreatic cancers harboring fusions involving NRG1, the gene encoding the high-affinity ligand neuregulin 1. NRG1 fusions lead to aberrant activation of HER3 signalling, making tumors exquisitely sensitive to HER3-targeted therapy. Zenocutuzumab’s design leverages this dependency by binding both HER3 and HER2, effectively blocking oncogenic signalling triggered by NRG1 fusions and recruiting immune effector functions. While NRG1 fusions occur rarely, their identification has spurred efforts to develop comprehensive genomic screening approaches to detect these patients and bring precision therapies to those with otherwise limited treatment options.
At the molecular level, HER3’s oncogenic role involves its capacity to bridge extracellular ligand binding and intracellular signalling networks that regulate key pathways such as PI3K/AKT and MAPK. Despite its own enzymatic shortcomings, HER3’s intracellular domains contain multiple tyrosine residues that become phosphorylated upon dimerization. This phosphorylation creates docking sites for critical adaptor proteins and enzymes that propagate survival and proliferation signals. Importantly, HER3 mutations, though relatively infrequent, can potentiate this signalling axis. Oncogenic somatic mutations in HER3 have been uncovered in various cancers, some of which lead to ligand-independent activation, further complicating therapeutic targeting and emphasizing the need for detailed molecular profiling.
HER3’s implication in resistance mechanisms represents another significant frontier. Clinical resistance to EGFR and HER2 inhibitors, which limit the durability of these therapies, frequently involves compensatory upregulation or activation of HER3. This receptor’s ability to rescue signalling pathways under pharmacologic pressure underscores its role as a critical node in adaptive resistance networks. Consequently, combining HER3-targeted therapies with existing HER family inhibitors or other targeted agents has become an attractive strategy to overcome or delay resistance. Early clinical data encourage this combinational approach, hinting at improved patient outcomes through co-targeting of interconnected signalling pathways.
Beyond direct cancer cell signalling, emerging research highlights intriguing links between HER3 and the tumour immune microenvironment. HER3-driven oncogenic signalling can modulate the expression of immune checkpoint molecules, cytokines, and chemokines, potentially shaping immune cell infiltration and function within tumors. This immunomodulatory role of HER3 adds layers of complexity but also opportunity, as HER3-targeted therapies may synergize with immunotherapies. Understanding the crosstalk between HER3 signalling and immune dynamics could pave the way for novel combination regimens that harness both targeted and immune-mediated antitumour responses.
The preclinical and early clinical successes of antibody–drug conjugates targeting HER3 have prompted vigorous exploration of various payloads and linker technologies to optimize therapeutic indices. ADCs encompassing HER3-specific antibodies coupled to microtubule inhibitors or DNA-damaging agents are being evaluated extensively. These approaches aim to selectively eradicate HER3-expressing tumor cells while sparing normal tissues, thereby offering an improved safety profile. The expanding ADC pipeline reflects confidence in HER3 as a target and holds promise for delivering breakthroughs in cancers where current treatment options remain inadequate.
Integral to advancing HER3-targeted therapy is the implementation of robust biomarker strategies. Identifying patients who will most likely benefit relies on sensitive and specific assays to detect HER3 expression levels, activating mutations, and especially NRG1 fusions. Contemporary genomic techniques, including next-generation sequencing and RNA-based fusion panels, have enabled more precise stratification of patients. Incorporating these diagnostics into clinical workflows is essential to realizing the full potential of HER3-directed agents and ensuring personalized treatment approaches.
Looking ahead, ongoing clinical trials are expanding the scope of HER3-targeted therapeutics beyond NSCLC and pancreatic cancers, investigating utility in breast, colorectal, and other solid tumors. Early signals suggest that even tumors without canonical NRG1 fusions may exhibit vulnerabilities to HER3 blockade, particularly in the context of combination therapies. This broadening horizon underscores the concept that HER3 is not merely a passenger in oncogenesis but a driver with context-dependent importance and therapeutic relevance.
Nonetheless, challenges persist. The intricate biology of HER3, including its regulatory feedback loops and intersection with multiple signaling axes, demands sophisticated therapeutic designs. Overcoming tumor heterogeneity, managing resistance, and minimizing toxicity while maintaining efficacy will require continued innovation in drug development. Furthermore, elucidating the interplay between HER3 and the immune system may uncover both obstacles and opportunities, necessitating multidisciplinary research efforts.
In summary, after years of setbacks and underappreciation, HER3 has ascended as a formidable target in oncology. Its intricate signalling capabilities, role in tumor progression, drug resistance, and immune modulation make it a compelling focus for new therapeutic modalities. The FDA accelerated approval of zenocutuzumab signals a watershed moment, opening the door to a new class of precision medicines that exploit HER3 dependencies. As clinical experience and molecular understanding deepen, HER3-targeted therapies are poised to reshape the cancer treatment landscape, offering hope for improved outcomes in patients with diverse and challenging malignancies.
As our knowledge of HER3 biology expands, so too does the complexity revealed within oncogenic signalling networks. HER3 embodies the dynamic adaptability of cancer cells, co-opting physiological mechanisms to drive malignancy. Future research aimed at dissecting its multifaceted roles promises to unearth novel therapeutic targets and synergistic combinations. The story of HER3 exemplifies the evolution of cancer therapeutics from broad-spectrum cytotoxic agents to precisely engineered molecules tailored to the molecular idiosyncrasies of individual tumors. In this evolving paradigm, HER3 stands as both a challenge and an opportunity — a biomolecular enigma whose unraveling could unlock transformative advances in cancer care.
Subject of Research:
HER3 receptor tyrosine kinase, its role in tumorigenesis, oncogenic signalling, and therapeutic targeting in cancer medicine.
Article Title:
Emerging importance of HER3 in tumorigenesis and cancer therapy.
Article References:
Garrett, J.T., Tendler, S., Feroz, W. et al. Emerging importance of HER3 in tumorigenesis and cancer therapy.
Nat Rev Clin Oncol 22, 348–370 (2025). https://doi.org/10.1038/s41571-025-01008-y
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