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ERBB2D16 Expression in HER2 Positive Gastric Cancer Is Associated With Resistance to Trastuzumab

Shuo Wang1, Yuze Zhao1, Yuguang Song1

  • 1Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.

Frontiers in Oncology
|April 25, 2022
PubMed

Insights

The ERBB2ΔEx16 (ERBB2d16) isoform promotes gastric cancer progression by driving epithelial-mesenchymal transition (EMT) and immune evasion. High ERBB2d16 levels correlate with poor response to trastuzumab therapy and shorter survival in HER2+ gastric cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • The ERBB2ΔEx16 (ERBB2d16) isoform of human epidermal growth factor receptor-2 (ERBB2, formerly HER2) is implicated in oncogenesis, immune evasion, and resistance to trastuzumab therapy.
  • Its specific role and prognostic significance in HER2-positive (HER2+) gastric cancer remain largely uncharacterized.

Purpose of the Study:

  • To investigate the expression of the ERBB2d16 isoform in gastric cancer tissues.
  • To evaluate the association between ERBB2d16 expression, epithelial-mesenchymal transition (EMT) markers, tumor immune infiltration, and patient response to trastuzumab-based therapy.
  • To determine the prognostic value of ERBB2d16 in HER2+ gastric cancer.

Main Methods:

  • Analysis of ERBB2d16 expression, EMT markers (E-cadherin, vimentin), CD3+ T cell infiltration, and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) expression in tumor tissues from 110 HER2+ gastric cancer patients.
  • Correlation of these markers with treatment response (RECIST criteria) and survival outcomes (progression-free and overall survival).
  • Statistical analysis using Cox proportional hazards models.

Main Results:

  • The ERBB2d16 isoform was detected in 53% (53/110) of gastric cancer samples.
  • An elevated ERBB2d16/ERBB2 ratio was associated with increased E-cadherin, decreased vimentin (indicating EMT), reduced CD3+ T cell infiltration, and higher PD-1/PD-L1 expression.
  • Patients with a high ERBB2d16/ERBB2 ratio exhibited significantly shorter progression-free and overall survival following trastuzumab treatment.
  • High ERBB2d16 expression was identified as a risk factor for adverse prognosis.

Conclusions:

  • ERBB2d16 plays an oncogenic role in gastric cancer by promoting EMT and immune suppression.
  • ERBB2d16 expression contributes to resistance to trastuzumab-induced cell death.
  • The ERBB2d16/ERBB2 ratio may serve as a novel prognostic biomarker for HER2+ gastric cancer patients receiving trastuzumab therapy.
Keywords:
ERBB2d16epithelial-mesenchymal transitiongastric cancerimmunosuppressiontrastuzumab resistance

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