ArticleProceedings of the National Academy of Sciences of the United States of America2002
Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 257 citations in OpenAlex.
- Molecular analysis of chronic eosinophilic leukemia with t(4;10) showing good response to imatinib mesylate.International journal of hematology · 2006Trial
- Lack of clinical efficacy of imatinib in metastatic melanoma.British journal of cancer · 2005Trial
- Non-Classical Binding Mechanisms of Ferrocene-Modified Imatinib and Nilotinib Analogues in BCR-ABL1 Kinase Revealed by Computational Analysis.Molecules (Basel, Switzerland) · 2026Article
- TAM family kinases are potential candidate targets for therapeutic intervention in chronic myeloid leukemia.Discover oncology · 2025Article
- Significance of Somatic Mutation Profiling in CML Beyond BCR-ABL: A Retrospective Study of the Indian Population.Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion · 2025Article
- Binding Affinity Determination in Drug Design: Insights from Lock and Key, Induced Fit, Conformational Selection, and Inhibitor Trapping Models.International journal of molecular sciences · 2024Review
- Inhibitor Trapping in Kinases.International journal of molecular sciences · 2024Article
- BCR-ABL kinase domain mutations in CML patients, experience from a tertiary care center in North India.Leukemia research reports · 2024Article
- MYC and therapy resistance in cancer: risks and opportunities.Molecular oncology · 2022Review
- Mapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers.Nature communications · 2022Article
- Potential ApproachesFrontiers in oncology · 2021Review
- Discovering and validating cancer genetic dependencies: approaches and pitfalls.Nature reviews. Genetics · 2020Review
- Conformational states dynamically populated by a kinase determine its function.Science (New York, N.Y.) · 2020Article
- Cumulative mechanism of several major imatinib-resistant mutations in Abl kinase.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Review
- Post-translational modifications at the ATP-positioning G-loop that regulate protein kinase activity.Pharmacological research · 2018Review
- Translocation of heme oxygenase-1 contributes to imatinib resistance in chronic myelogenous leukemia.Oncotarget · 2017Article
- RETRACTED: Blockade of Y177 and Nuclear Translocation of Bcr-Abl Inhibits Proliferation and Promotes Apoptosis in Chronic Myeloid Leukemia Cells.International journal of molecular sciences · 2017Article
- Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.Haematologica · 2017Article
- MultipleMolecular cytogenetics · 2017Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The Abl tyrosine kinase inhibitor STI-571 is effective therapy for stable phase chronic myeloid leukemia (CML) patients, but the majority of CML blast-crisis patients that respond to STI-571 relapse because of reactivation of Bcr-Abl signaling. Mutations of Thr-315 in the Abl kinase domain to Ile (T315I) were previously described in STI-571-resistant patients and likely cause resistance from steric interference with drug binding. Here we identify mutations of Tyr-253 in the nucleotide-binding (P) loop of the Abl kinase domain to Phe or His in patients with advanced CML and acquired STI-571 resistance. Bcr-Abl Y253F demonstrated intermediate resistance to STI-571 in vitro and in vivo when compared with Bcr-Abl T315I. The response of Abl proteins to STI-571 was influenced by the regulatory state of the kinase and by tyrosine phosphorylation. The sensitivity of purified c-Abl to STI-571 was increased by a dysregulating mutation (P112L) in the Src homology 3 domain of Abl but decreased by phosphorylation at the regulatory Tyr-393. In contrast, the Y253F mutation dysregulated c-Abl and conferred intrinsic but not absolute resistance to STI-571 that was independent of Tyr-393 phosphorylation. The Abl P-loop is a second target for mutations that confer resistance to STI-571 in advanced CML, and the Y253F mutation may impair the induced-fit interaction of STI-571 with the Abl catalytic domain rather than sterically blocking binding of the drug. Because clinical resistance induced by the Y253F mutation might be overcome by dose escalation of STI-571, molecular genotyping of STI-571-resistant patients may provide information useful for rational therapeutic management.
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