ArticleOncotarget2016
Identification of a structurally novel BTK mutation that drives ibrutinib resistance in CLL.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 89 citations in OpenAlex.
- Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents.Frontiers in oncology · 2020Pooled it
- Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial.Blood · 2018Trial
- Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia.Blood · 2017Trial
- Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases.MedComm · 2026Review
- Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies.Molecular therapy. Oncology · 2026Review
- Mechanisms of resistance to bruton's tyrosine kinase inhibitors: synergistic effects of tumor microenvironment regulation and signaling pathways.Annals of hematology · 2026Review
- Evaluation of the Role of AID-Induced Mutagenesis in Resistance to B-Cell Receptor Pathway Inhibitors in Chronic Lymphocytic Leukemia.Current issues in molecular biology · 2025Article
- BTK autoinhibition analyzed by high-throughput swaps of SH2 domains.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Resistance mechanisms and approach to chronic lymphocytic leukemia after BTK inhibitor therapy.Leukemia & lymphoma · 2025Review
- Article
- Comparative Analysis of Osteoarthritis Therapeutics: A Justification for Harnessing Retrospective Strategies via an Inverted Pyramid Model Approach.Biomedicines · 2024Review
- Recent Advances in the Molecular Biology of Chronic Lymphocytic Leukemia: How to Define Prognosis and Guide Treatment.Cancers · 2024Review
- The Evolving Role of Bruton's Tyrosine Kinase Inhibitors in B Cell Lymphomas.International journal of molecular sciences · 2024Review
- Review
- Treatment Sequencing in Chronic Lymphocytic Leukemia in 2024: Where We Are and Where We Are Headed.Cancers · 2024Review
- Review
- A Review of Resistance Mechanisms to Bruton's Kinase Inhibitors in Chronic Lymphocytic Leukemia.International journal of molecular sciences · 2024Review
- Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL).Genes · 2023Review
- Pirtobrutinib in Covalent Bruton Tyrosine Kinase Inhibitor Pretreated Mantle-Cell Lymphoma.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2023Article
- Assessment of Impact of Human Leukocyte Antigen-Type and Cytokine-Type Responses on Outcomes after Targeted Therapy Currently Used to Treat Chronic Lymphocytic Leukemia.Journal of clinical medicine · 2023Review
Corrections and comments
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Authors and funding
16 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ibrutinib (ibr), a first-in-class Bruton tyrosine kinase (BTK) inhibitor, has demonstrated high response rates in both relapsed/refractory and treatment naïve chronic lymphocytic leukemia (CLL). However, about 25% of patients discontinue ibrutinib therapy at a median follow-up of 20 months and many patients discontinue the treatment due to leukemia progression or Richter transformation. Mutations affecting the C481 residue of BTK disrupt ibrutinib binding and have been characterized by us and others as the most common mechanism of ibrutinib resistance. Thus far, all described BTK mutations are located in its kinase domain and mutations outside this domain have never been described. Herein, we report a patient whose CLL progressed, was salvaged with ibrutinib and then relapsed. Serial analysis of samples throughout patient's clinical course identified a structurally novel mutation (BTKT316A) in the SH2 domain, but not kinase domain, of Bruton tyrosine kinase which was associated with disease relapse. Functionally, cells carrying BTKT316A show resistance to ibrutinib at both cellular and molecular levels to a similar extent as BTKC481S. Our study lends further insight into the diverse mechanisms of ibrutinib resistance that has important implications for the development of next-generation BTK inhibitors as well as mutation detection in relapsed patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.