Neuregulin 1–Human Epidermal Growth Factor Receptor 3 interface (NRG1–HER3 interface)

The Neuregulin 1–Human Epidermal Growth Factor Receptor 3 (NRG1–HER3) interface is a critical protein-protein interaction site involved in the activation of the ErbB signaling pathway. Neuregulin 1 (NRG1) acts as a ligand that binds to the extracellular domain of HER3 (ERBB3), inducing a conformational change that facilitates its heterodimerization with other ErbB family members, most notably HER2 (ERBB2) [UniProt: P21860, Q02297]. Because HER3 possesses minimal intrinsic kinase activity, this dimerization is essential for the recruitment and activation of the PI3K/Akt/mTOR signaling cascade, which drives cell survival, growth, and differentiation [PubMed: 29215118]. In various cancers, particularly those harboring NRG1 gene fusions, the overproduction or constitutive presence of the NRG1 ligand leads to hyperactivation of the HER3 receptor, promoting aggressive tumor growth and resistance to standard therapies [PubMed: 31064754]. Therapeutic targeting of this interface involves the use of monoclonal or bispecific antibodies designed to block NRG1 binding or prevent the subsequent dimerization of HER3 with HER2 [PubMed: 33879461]. Drugs like zenocutuzumab specifically target this interface to inhibit oncogenic signaling in patients with NRG1-fusion-positive tumors, such as non-small cell lung cancer and pancreatic cancer [ClinicalTrials.gov: NCT02912949]. This interface is a high-priority target in precision oncology due to the specific dependency of NRG1-fusion-positive cells on this signaling axis. Clinical challenges include identifying patients through advanced genomic sequencing and managing toxicities related to the inhibition of physiological ErbB signaling.

Other names

NRG1–ERBB3 interfaceNeuregulin 1–ErbB3 complexNRG1–HER3 binding siteNRG1–HER3 interaction site

Competitive inhibition of NRG1 binding to the HER3 extracellular domain, prevention of HER3/HER2 heterodimerization, and subsequent inhibition of the PI3K/Akt/mTOR signaling pathway.