ArticleJournal of molecular modeling2015
Computationally unraveling how ceritinib overcomes drug-resistance mutations in ALK-rearranged lung cancer.
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 12 papers.
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Who cites it
12 citing papers in PubMed, 17 citations in OpenAlex.
- Revealing GRK5 Activation Features by Interpretable Machine Learning and Molecular Dynamics Simulation.International journal of molecular sciences · 2026Article
- Mechanisms of Resistance to ALK Inhibitors and Corresponding Treatment Strategies in Lung Cancer.International journal of general medicine · 2025Review
- Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.MedComm · 2024Review
- Comparative Atomistic Insights on Apo and ATP-I1171N/S/T in Nonsmall-Cell Lung Cancer.ACS omega · 2023Article
- 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
- Ceritinib Treatment for Carcinomatous Meningitis with a Secondary Mutation at I1171T in Anaplastic Lymphoma Kinase.Internal medicine (Tokyo, Japan) · 2018Article
- Computational dissection of allosteric inhibition of the SH2 domain of Bcr-Abl kinase by the monobody inhibitor AS25.Journal of molecular modeling · 2017Article
- Mutation testing for directing upfront targeted therapy and post-progression combination therapy strategies in lung adenocarcinoma.Expert review of molecular diagnostics · 2016Review
- TKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumors.Oncotarget · 2016Article
- ALK and ROS1 as targeted therapy paradigms and clinical implications to overcome crizotinib resistance.Oncotarget · 2016Review
- New treatment options for ALK+ advanced non-small-cell lung cancer: critical appraisal of ceritinib.Therapeutics and clinical risk management · 2016Review
- Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for Ceritinib.Pharmacogenomics and personalized medicine · 2015Review
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, has been implicated in the pathogenesis of several cancers. The small molecule ceritinib can overcome drug-resistance mutations that are observed in crizotinib-resistant patients, although the detailed mechanism for this ability of ceritinib remains elusive. Here, molecular dynamics (MD) simulations of six systems (including the apo ALK, the wild-type ALK-ceritinib complex, as well as four complexes of ceritinib with the I1171T, L1196M, S1206Y, and G1269A mutants of ALK, respectively) together with the subsequent molecular mechanics-generalized Born/surface area binding free energy calculations were performed to answer this question. Principal component analysis and domain cross-correlation analysis of MD trajectories revealed that ceritinib binding stabilized the conformational dynamics of both the wild-type and the four mutated ALKs as compared to the apo ALK. Moreover, the mutations had subtle effects on the conformation of ALK compared to that of the wild-type ALK. Importantly, binding free energy calculations demonstrated that, compared its effect on the wild-type ALK, ceritinib showed slightly increased potency towards the I1171T, L1196M, S1206Y, and G1269A mutants. Therefore, the binding of ceritinib to the four mutants can overcome crizotinib-resistant mutations. These data provide a structural and energetic explanation of how ceritinib overcomes mutation-induced drug resistance.
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