ArticleProceedings of the National Academy of Sciences of the United States of America2020
Cumulative mechanism of several major imatinib-resistant mutations in Abl kinase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 56 citations in OpenAlex.
- Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1.Genome medicine · 2026Article
- The Discovery of Abl Kinase ATPase Activity and Its Implications in the Development of Straightforward Assays.ACS omega · 2025Article
- The Mechanisms of Resistance to JAK Inhibitors in Lymphoid Leukemias: A Scoping Review of Evidence from Preclinical Models and Case Reports.International journal of molecular sciences · 2025Article
- Post-marketing safety signals of imatinib: pharmacovigilance insights from the FDA Adverse Event Reporting System (FAERS) and implications for clinical practice.European journal of clinical pharmacology · 2025Article
- A microRNA-based dynamic risk score for type 1 diabetes.Nature medicine · 2025Article
- The end of the genetic paradigm of cancer.PLoS biology · 2025Review
- Occurrence of Existing BCR-ABL Baseline Mutations and Associated Haplotype (NmR) Among CML Patients with Diverse IM Response: A Hospital-based Study from North-East India.Biochemical genetics · 2024Article
- High-throughput prediction of protein conformational distributions with subsampled AlphaFold2.Nature communications · 2024Article
- Potts Hamiltonian Models and Molecular Dynamics Free Energy Simulations for Predicting the Impact of Mutations on Protein Kinase Stability.The journal of physical chemistry. B · 2024Article
- Identification by molecular dynamic simulation and in vitro validation of SISB-A1, N-[1-(4-bromophenyl)-3-methyl-1H-pyrazol-5-yl]-2-[(2-oxo-4-phenyl-2H-chromen-7-yl) oxy], as an inhibitor of the AblMedical oncology (Northwood, London, England) · 2023Article
- Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer.Cancer research · 2023Article
- Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations.Nature communications · 2022Article
- Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective.Signal transduction and targeted therapy · 2022Review
- Protein Flexibility and Dissociation Pathway Differentiation Can Explain Onset of Resistance Mutations in Kinases.Angewandte Chemie (International ed. in English) · 2022Article
- Evaluation of residue variability in a conformation-specific context and during evolutionary sequence reconstruction narrows drug resistance selection in Abl1 tyrosine kinase.Protein science : a publication of the Protein Society · 2022Article
- Mapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers.Nature communications · 2022Article
- A novel imatinib-upregulated long noncoding RNA plays a critical role in inhibition of tumor growth induced by Abl oncogenes.Molecular cancer · 2022Article
- Activation of Abl1 Kinase Explored Using Well-Tempered Metadynamics Simulations on an Essential Dynamics Sampled Path.Journal of chemical theory and computation · 2021Article
- Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells.Journal of hematology & oncology · 2021Article
- Computer Simulations of the Dissociation Mechanism of Gleevec from Abl Kinase with Milestoning.The journal of physical chemistry. B · 2021Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Despite the outstanding success of the cancer drug imatinib, one obstacle in prolonged treatment is the emergence of resistance mutations within the kinase domain of its target, Abl. We noticed that many patient-resistance mutations occur in the dynamic hot spots recently identified to be responsible for imatinib's high selectivity toward Abl. In this study, we provide an experimental analysis of the mechanism underlying drug resistance for three major resistance mutations (G250E, Y253F, and F317L). Our data settle controversies, revealing unexpected resistance mechanisms. The mutations alter the energy landscape of Abl in complex ways: increased kinase activity, altered affinity, and cooperativity for the substrates, and, surprisingly, only a modestly decreased imatinib affinity. Only under cellular adenosine triphosphate (ATP) concentrations, these changes cumulate in an order of magnitude increase in imatinib's half-maximal inhibitory concentration (IC
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