ArticleJournal of molecular modeling2015
Atomistic insights into the lung cancer-associated L755P mutation in HER2 resistance to lapatinib: a molecular dynamics study.
Article in Journal of molecular modeling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 18 citations in OpenAlex.
- Poziotinib for Patients WithJournal of clinical oncology : official journal of the American Society of Clinical Oncology · 2022Trial
- Biomarker Analysis of the Phase III NALA Study of Neratinib + Capecitabine versus Lapatinib + Capecitabine in Patients with Previously Treated Metastatic Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Trial
- Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity.Cancer cell · 2019Trial
- Comprehensive Molecular Docking and Molecular Dynamics Reveal Inhibitors of HER2 L755S, T798I, and T798M based on a Large Database of Curcumin Derivatives.Asian Pacific journal of cancer prevention : APJCP · 2026Article
- High-throughput characterization of 5886 HER2 variants identifies 112 new in cellulo gain-of-function mutations.Genomics · 2025Article
- New Gain-of-Function Mutations Prioritize Mechanisms of HER2 Activation.medRxiv : the preprint server for health sciences · 2025Article
- Computational molecular insights into ibrutinib as a potent inhibitor of HER2-L755S mutant in breast cancer: gene expression studies, virtual screening, docking, and molecular dynamics analysis.Frontiers in molecular biosciences · 2025Article
- Review
- Computational dissection of allosteric inhibition of the SH2 domain of Bcr-Abl kinase by the monobody inhibitor AS25.Journal of molecular modeling · 2017Article
- HER2 missense mutations have distinct effects on oncogenic signaling and migration.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Computationally unraveling how ceritinib overcomes drug-resistance mutations in ALK-rearranged lung cancer.Journal of molecular modeling · 2015Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
HER2, a member of the human ErbB protein family belonging to receptor tyrosine kinases, plays important roles in regulating crucial cellular processes, including cell migration, proliferation, and differentiation. A missense mutation, L755P, in the HER2 kinase domain has been involved in lung cancer in humans and exhibits reduced response to lapatinib therapy. However, the detailed mechanism of how the HER2 L755P mutation causes drug resistance to lapatinib remains elusive. Here, molecular docking, molecular dynamics (MD) simulations, binding free energy calculations [molecular mechanics and generalized Born/surface area (MM-GBSA)] were performed to reveal the mechanism of drug resistance due to the HER2 L755P mutation. MD simulations revealed that the L755P mutation caused structural changes in the regions of helix αC, the glycine-rich loop, and the activation loop, thereby leading to the loss of interactions between the solubilizing group of lapatinib and HER2. Moreover, MM-GBSA calculations suggested that hydrophobic interactions between lapatinib and HER2 contribute most to the binding affinity, and that the L755P mutation could result in a less energetically favorable HER2/lapatinib complex. This may weaken the binding of lapatinib to the mutated HER2, thereby leading to the emergence of drug resistance. This study offers a structural explanation for the effect of the L755P mutation on the HER2/lapatinib complex.
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