Human epidermal growth factor receptor 2 (HER2) exon 20 insertion mutants (HER2 exon 20 ins)

Human epidermal growth factor receptor 2 (HER2) exon 20 insertion mutants are oncogenic drivers found in approximately 2-4% of non-small cell lung cancers (NSCLC) (Robichaux et al., 2018, Nature Genetics). These mutations involve in-frame insertions within the kinase domain, most commonly the YVMA (A775_G776insYVMA) variant, which lead to constitutive, ligand-independent activation of the receptor and downstream proliferative signaling through the PI3K/AKT and MAPK pathways (Zhou et al., 2021, JCO). Unlike HER2 amplification or overexpression common in breast cancer, these insertions alter the ATP-binding pocket, often conferring resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) (Heydt et al., 2019, Annals of Oncology). The therapeutic landscape has shifted with the FDA approval of the antibody-drug conjugate trastuzumab deruxtecan, which targets the receptor to deliver a cytotoxic payload directly to the tumor cells (Li et al., 2022, NEJM). Management of these patients requires precise molecular profiling via next-generation sequencing (NGS) to distinguish these insertions from other HER2 alterations, as traditional immunohistochemistry often fails to identify them (Burnett et al., 2021, JTO).

Other names

ERBB2 exon 20 insertionsHER2 YVMAA775_G776insYVMAHER2 kinase domain insertionsNeu exon 20 insertion

Targeted inhibition of the constitutively active tyrosine kinase domain or receptor-mediated delivery of cytotoxic payloads via antibody-drug conjugates.