ArticleJournal of molecular modeling2017
Exploring the crizotinib resistance mechanism of NSCLC with the L1196M mutation using molecular dynamics simulation.
Article in Journal of molecular modeling, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including Lorlatinib-Resistant Compound Mutations.Cancer discovery · 2024Trial
- Targeting FLT3 in Acute Myeloid Leukemia: Structural Insights and Key Challenges.ACS bio & med chem Au · 2026Review
- Anaplastic large cell lymphoma in children and adolescents.British journal of haematology · 2025Review
- Review
- Acquired L1196MEJHaem · 2023Article
- Evaluation of Lorlatinib Cerebrospinal Fluid Concentrations in Relation to Target Concentrations for Anaplastic Lymphoma Kinase (ALK) Inhibition.Journal of clinical pharmacology · 2022Article
- An insight into lung cancer: a comprehensive review exploring ALK TKI and mechanisms of resistance.Bosnian journal of basic medical sciences · 2022Review
- Article
- Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase.Frontiers in cell and developmental biology · 2021Article
- Article
- Complex Oncological Decision-Making Utilizing Fast-and-Frugal Trees in a Community Setting-Role of Academic and Hybrid Modeling.Journal of clinical medicine · 2020Article
- Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing.OncoTargets and therapy · 2020Article
- Xenograft tumors derived from malignant pleural effusion of the patients with non-small-cell lung cancer as models to explore drug resistance.Cancer communications (London, England) · 2018Article
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Authors and funding
2 authors.
Funding
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Abstract
Crizotinib is an anticancer tyrosine kinase inhibitor that is approved for use as a first-line treatment for some non-small-cell lung cancers. L1196M is the most frequently observed mutation in NSCLC patients. This mutation, known as the gatekeeper mutation in the ALK kinase domain, confers resistance to crizotinib by sterically blocking the binding of the drug. However, the molecular mechanism of crizotinib resistance caused by the L1196M mutation is still unclear. Molecular dynamics simulation was therefore utilized in this study to investigate the mechanism by which the L1196M mutation may affect crizotinib resistance. Our results suggest that larger fluctuations in some important regions of the mutant complex compared to the wild-type complex may contribute to the resistance of the mutant complex to crizotinib. Also, mutation-induced alterations to the secondary structure of the complex as well as unstable hydrogen-bonding patterns in the A-loop and P-loop regions decrease the total binding energy of the complex. This study therefore provides a molecular explanation for the resistance to crizotinib caused by the L1196M mutation, which could aid the design of more efficient and selective drugs.
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