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Background <p>Human epidermal growth factor receptor-2 (HER2)-positive breast cancer is characterized by aggressive tumor progression and reduced survival, primarily due to the overexpression of the <i>ERBB2</i> gene. Herceptin (trastuzumab), a monoclonal antibody&#xa0;(mAb) targeting the extracellular domain (ECD) of the HER2 receptor, significantly improves patient outcomes. However, the presence of non-synonymous single-nucleotide polymorphisms (nsSNPs) within the HER2 ECD may alter the therapeutic efficacy of Herceptin by affecting its&#xa0;interaction with the receptor.</p> Methods <p>This study employed an in silico approach to identify damaging nsSNPs within the HER2 ECD using five prediction tools (PolyPhen-2, SIFT, SNAP2, PhD-SNP, and SNPs and GO). The structural and functional impacts of the selected variants were assessed through protein stability prediction, evolutionary conservation analysis, posttranslational modification (PTM) profiling, and 3D modeling. Molecular docking and molecular dynamics (MD) simulations were performed to evaluate changes in Herceptin binding affinity and complex stability for wild-type and variant HER2 receptors.</p> Results <p>Out of 554&#xa0;nsSNPs, 139 damaging mutations were identified within the ECD&#xa0;of HER2. Structural modeling and docking analyses showed that these variants alter Herceptin binding energies, with E40K enhancing and G201V diminishing the drug&#xa0;affinity the most. MD simulations confirmed these effects, with E40K stabilizing and G201V destabilizing the HER2–Herceptin complex. Alterations in the root mean square deviation (RMSD), solvent-accessible surface area (SASA), and free energy landscapes supported these observations, highlighting distinct conformational behaviors for each variant.</p> Conclusion <p>Damaging nsSNPs within the HER2 ECD significantly influences the structural integrity and drug-binding dynamics of the HER2–Herceptin complex. Variants such as G201V may compromise therapeutic efficacy, underscoring the importance of genetic screening for <i>ERBB2</i> in HER2-positive patients. Personalized treatment strategies based on mutation profiling could optimize Herceptin responsiveness and inspire the development of next-generation HER2-targeted therapies.</p>

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Damaging non-synonymous mutations in the extracellular domain of HER2 potentially alter the efficacy of Herceptin-mediated breast cancer therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月5日

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  • Arijit Samanta,
  • Anisha Karim,
  • Ashif Ahamed,
  • Md Kamal Hassan,
  • Syed Sahajada Mahafujul Alam,
  • Safdar Ali,
  • Mehboob Hoque

摘要

Background

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer is characterized by aggressive tumor progression and reduced survival, primarily due to the overexpression of the ERBB2 gene. Herceptin (trastuzumab), a monoclonal antibody (mAb) targeting the extracellular domain (ECD) of the HER2 receptor, significantly improves patient outcomes. However, the presence of non-synonymous single-nucleotide polymorphisms (nsSNPs) within the HER2 ECD may alter the therapeutic efficacy of Herceptin by affecting its interaction with the receptor.

Methods

This study employed an in silico approach to identify damaging nsSNPs within the HER2 ECD using five prediction tools (PolyPhen-2, SIFT, SNAP2, PhD-SNP, and SNPs and GO). The structural and functional impacts of the selected variants were assessed through protein stability prediction, evolutionary conservation analysis, posttranslational modification (PTM) profiling, and 3D modeling. Molecular docking and molecular dynamics (MD) simulations were performed to evaluate changes in Herceptin binding affinity and complex stability for wild-type and variant HER2 receptors.

Results

Out of 554 nsSNPs, 139 damaging mutations were identified within the ECD of HER2. Structural modeling and docking analyses showed that these variants alter Herceptin binding energies, with E40K enhancing and G201V diminishing the drug affinity the most. MD simulations confirmed these effects, with E40K stabilizing and G201V destabilizing the HER2–Herceptin complex. Alterations in the root mean square deviation (RMSD), solvent-accessible surface area (SASA), and free energy landscapes supported these observations, highlighting distinct conformational behaviors for each variant.

Conclusion

Damaging nsSNPs within the HER2 ECD significantly influences the structural integrity and drug-binding dynamics of the HER2–Herceptin complex. Variants such as G201V may compromise therapeutic efficacy, underscoring the importance of genetic screening for ERBB2 in HER2-positive patients. Personalized treatment strategies based on mutation profiling could optimize Herceptin responsiveness and inspire the development of next-generation HER2-targeted therapies.