Targeting HER3 for cancer treatment: a new horizon for an old target

Abstract

Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptors family, having as its main ligands neuregulins 1 and 2. Although its poor tyrosine kinase activity entails a weak oncogenic power on its own, HER3 can heterodimerize with HER2 and/or epidermal growth factor receptor (EGFR), leading to a drastic enhancement of transphosphorylation and activation of downstream signaling pathways, ultimately promoting oncogenesis, metastatic dissemination, and drug resistance. Given its ubiquitous expression across solid tumors, multiple efforts have been done to therapeutically target HER3 by blocking either the ligand binding domain or its dimerization with other receptors. Treatment with anti-HER3 monoclonal antibodies or bispecific antibodies, both as single agents and in combination with other compounds, unfortunately led to unsatisfactory results across several tumor types. The HER3-directed delivery of cytotoxic payloads through antibody-drug conjugates has recently demonstrated encouraging activity in several tumor types, however, suggesting a potential role for the therapeutic targeting of HER3 in cancer treatment.

Keywords: ADCs; HER3; breast cancer; lung cancer; patritumab deruxtecan.

Figure 1

HER3 and its signaling pathway. (A) In its monomeric inactivated form, HER3, as the other highly homologous HER family proteins, consists of four structural components playing different key roles: (i) a ligand-binding extracellular domain, (ii) a transmembrane domain, (iii) an intracellular kinase domain, and (iv) a C-terminal tail. (B) The binding between NRG1-2 and HER3 induces a conformational change resulting in its heterodimerization preferentially with EGFR and HER2. This causes a further conformational modification in the intracellular domain, leading to the transphosphorylation of the C-terminal tails, which eventually activates downstream intracellular signaling pathways, such as PI3K/AKT, MAPK, JAK/STAT and SRC, regulating several cellular processes including cell division, proliferation, differentiation, as well as angiogenesis and tumor progression. AKT, protein kinase B; EGFR, epidermal growth factor receptor; GDP, guanosine diphosphate; GTP, guanosine triphosphate; GRB2, growth factor receptor bound protein 2; HER, human epidermal growth factor receptor; JAK, janus kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated extracellular signal-regulated kinase; NRG, neuregulin; PI3K, phosphoinositide-3 kinase; SOS, son of sevenless; STAT, signal transducer and activator of transcription.

Figure 2

Rate of HER3 overexpression across different tumor types. HNSCC, head and neck squamous cell carcinoma.

Figure 3

(A) Anti-HER3 therapeutic strategies. In the last decades, several anti-HER3 compounds with different mechanisms have been tested, unfortunately with disappointing results. Amongst them: MoAbs targeting HER3 preventing its heterodimerization with other receptors; bispecific Abs targeting both HER3 and EGFR or HER2 or IGF-1; the ADC patritumab-deruxtecan. (B) ORR of patritumab deruxtecan in pretreated mBC and advanced NSCLC. In BC, durable antitumor activity was observed across the range of HER3 expression in metastatic HR-positive/HER2-negative BC (ORR 30%; median DOR 7.2 months), TNBC (ORR 23%; median DOR 5.9 months) and HER2-positive BC (ORR 43%; median DOR 8.3 months) patients. In pretreated patients with EGFR-mutated and wild-type NSCLC, patritumab deruxtecan at the dose of 5.6 mg/kg achieved an ORR of 39% and 35%, respectively. ADC, antibody–drug conjugate; BC, breast cancer; DOR, duration of response; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; HR, hormone receptor; IGF-1, insulin-like growth factor-1; mBC, metastatic breast cancer; MoAb, monoclonal antibody; NSCLC, non-small-cell lung cancer; ORR, overall response rate; TNBC, triple-negative breast cancer.