ERBB2 – Lung Cancer

Lung cancer is the leading cause of cancer mortality worldwide and oncogenic somatic mutations in ERBB2 (HER2) occur in approximately 1.6% of non‐small cell lung cancers (PMID:15753357). These mutations are most commonly in‐frame insertions in exon 20 that activate kinase function, driving tumorigenesis and often co‐occurring with adenocarcinoma histology in never‐smokers.

Large cohort sequencing studies identified ERBB2 exon 20 insertions in 11 of 671 NSCLC cases (1.6%) (PMID:15753357) and in 13 of 504 Japanese adenocarcinomas (2.6%) (PMID:21353324). Subsequent series confirmed a prevalence of 1–3% in lung adenocarcinomas and noted mutual exclusivity with EGFR and KRAS driver mutations. Recurrent variants include c.2332_2340dup (p.Gly778_Pro780dup) and A775_G776insYVMA.

The variant spectrum is dominated by in‐frame exon 20 insertions, which disrupt an autoinhibitory αC‐β4 loop, stabilizing the active kinase conformation. These gain‐of‐function mutations exhibit enhanced autophosphorylation and downstream MAPK and PI3K-AKT pathway activation, consistent across independent tumor cohorts.

In vitro and in vivo functional assays demonstrate that ERBB2 exon 20 insertion mutants transform NIH 3T3 cells, drive tumor formation in xenografts, and preferentially phosphorylate substrates such as GAB1 (PMID:24317180). Structural and kinetic analyses reveal a 7–10-fold increase in catalytic turnover and ATP affinity attributable to loop destabilization (PMID:24317180).

Clinically, patients with ERBB2 exon 20 insertions respond to HER2‐targeted therapies: afatinib elicited durable partial responses in cases harboring the YVMA insertion (PMID:26559459). Resistance mechanisms include activation of bypass pathways, underscoring the need for combination strategies.

Spatial and temporal heterogeneity of resistance emphasizes comprehensive molecular monitoring. ERBB2 mutations remain largely mutually exclusive with other lung cancer drivers, reinforcing their role as primary oncogenic events.

In summary, somatic ERBB2 exon 20 insertions constitute a strong, actionable driver in lung adenocarcinoma, supporting their inclusion in diagnostic panels and guiding targeted therapy selection.

References

• Cancer research • 2005 • Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. PMID:15753357
• Lung cancer (Amsterdam, Netherlands) • 2011 • Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers. PMID:21353324
• Journal of the National Cancer Institute • 2014 • Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas. PMID:24317180
• Lung cancer (Amsterdam, Netherlands) • 2015 • HER2 insertion YVMA mutant lung cancer: Long natural history and response to afatinib. PMID:26559459

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