Abstract
HER3 is a member of the HER/ErbB family of receptor tyrosine kinases, together with EGFR (HER1), HER2 and HER4. Despite having only weak intrinsic kinase activity, HER3 can contribute to oncogenic signalling via ligand-induced heterodimerization with other HER family members. Evidence indicates that HER3 is altered or aberrantly expressed across a variety of tumour types and can be associated with poor clinical outcomes. Whereas anticancer agents targeting EGFR and HER2 have been approved for decades, no drug targeting HER3 had been approved until very recently. Initial targeting of HER3 with monoclonal antibodies as single agents or in combination with other therapeutics produced disappointing clinical results. Subsequently, efforts have been made to target HER3 with novel agents such as antibody–drug conjugates and bispecific antibodies, with promising efficacy observed in several trials encompassing various tumour types. In December 2024, the HER3 × HER2 bispecific antibody zenocutuzumab was granted FDA Accelerated Approval for the treatment of non-small-cell lung cancers or pancreatic cancers harbouring fusions involving NRG1, the gene encoding the high-affinity HER3 ligand neuregulin 1. In this Review, we provide an essential guide to HER3 signalling and oncogenesis, HER3 expression in cancer and its prognostic implications, oncogenic HER3 somatic mutations as well as rare NRG1 fusions that might depend on HER3 signalling, and the roles of HER3 in resistance to cancer therapies. We also highlight efforts to target HER3 with diverse therapeutic strategies and the potential interplay between HER3 and the antitumour immune response.
Key points
HER3 expression is associated with a poor prognosis in patients with various solid tumour types and is linked to resistance to targeted therapies, including those targeting EGFR and HER2.
Although rare, tumours with NRG1 fusions seem to be particularly responsive to HER3-targeted therapies.
While HER3-targeted monoclonal antibodies have shown limited efficacy in clinical trials, HER3-targeted bispecific antibodies and antibody–drug conjugates have demonstrated more promising efficacy.
HER3-targeted therapies might be most effective in certain groups of patients, such as those with NRG1 fusion-positive tumours or EGFR-mutant non-small-cell lung cancer after progression on an EGFR tyrosine kinase inhibitor.
Studies aimed at identifying biomarkers of treatment response should be a key component of clinical trials testing HER3-targeted therapies.