Thirty Years of HER3: From Basic Biology to Therapeutic Interventions

Abstract

HER3 is a pseudokinase member of the EGFR family having a role in both tumor progression and drug resistance. Although HER3 was discovered more than 30 years ago, no therapeutic interventions have reached clinical approval to date. Because the evidence of the importance of HER3 is accumulating, increased amounts of preclinical and clinical trials with HER3-targeting agents are emerging. In this review article, we discuss the most recent HER3 biology in tumorigenic events and drug resistance and provide an overview of the current and emerging strategies to target HER3.

Figure 1:. HER3 dimerization and signaling cascade.

Upon ligand binding, HER3 preferentially dimerizes with EGFR or HER2 inducing a conformational change in the receptor pair. The conformational change leads into transphosphorylation event in the intracellular kinase tail, where the C-terminal tail of HER3 acts as an acceptor for multiple phosphorylations. This induces activation of signaling cascades promoting cell survival and proliferation. EGFR: Epidermal growth factor receptor, EGF: Epidermal growth factor, HER2: Human epidermal growth factor receptor 2, HER3: Human epidermal growth factor receptor 3, NRG: Neuregulin, p85: 85kDa regulator subunit of phosphoinositide 3-kinase, p110: 110kDa catalytic subunit of phosphoinositide 3-kinase, AKT: protein kinase B, SHC: SHC-transforming protein 1, GRB2: growth factor receptor bound protein 2, SOS: Son of sevenless, RAS: RAS GTPase, RAF: Raf kinase, MAPK: Mitogen-activated protein kinase.

Figure 2:. Therapeutic strategies to target HER3.

The most popular strategies to target HER3 have been monoclonal and bispecific antibodies, as well as pan-HER strategies. Emerging strategies to target HER3 include antibody drug conjugates, HER3-targeting vaccines, and different ways to affect HER3 degradation either in mRNA or protein level. Epigenetic inhibitors could potentially be useful for inhibiting HER3 gene expression, although the mechanisms and feasibility of these strategies will have to be further validated. EGFR: Epidermal growth factor receptor, HER2: Human epidermal growth factor receptor 2, HER3: Human epidermal growth factor receptor 3, NRG: Neuregulin, mAbs: Monoclonal antibodies, IGFR: Insulin-like growth factor receptor. DXd: DX-8951 derivative.