Receptor tyrosine-protein kinase erbB-2 (ERBB2) mutants (HER2 mutants)

Receptor tyrosine-protein kinase erbB-2 (ERBB2), commonly known as HER2, is a member of the epidermal growth factor receptor (EGFR) family that plays a pivotal role in cell growth and survival signaling [1][2]. Unlike other members of its family, HER2 lacks a known high-affinity ligand and exists in a constitutively active conformation, making it the preferred dimerization partner for other EGFR receptors [2][6]. Mutations in the ERBB2 gene, particularly exon 20 insertions and point mutations in the kinase or extracellular domains, lead to ligand-independent activation of downstream pathways such as PI3K/AKT and MAPK/ERK [3][5]. These mutations are distinct from HER2 amplification and are recognized as critical oncogenic drivers in several malignancies, most notably non-small cell lung cancer (NSCLC) [3][4]. Therapeutic strategies specifically targeting HER2 mutants include small-molecule tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) like trastuzumab deruxtecan, which has been approved for treating HER2-mutant NSCLC [4][5]. Clinical management of these therapies requires monitoring for significant safety concerns, including interstitial lung disease and cardiotoxicity [4][6].

Other names

ERBB2 mutantsHER-2/neu mutantsCD340 mutantsProto-oncogene Neu mutantsHER2 mutationsERBB2 mutations

Inhibition of receptor tyrosine kinase activity, disruption of downstream signaling pathways (PI3K/AKT, MAPK/ERK), and targeted delivery of cytotoxic agents via antibody-drug conjugates [4][5].