ArticleLeukemia2017
Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant.
Article in Leukemia, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 57 citations in OpenAlex.
- Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents.Frontiers in oncology · 2020Pooled it
- Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia.Blood · 2017Trial
- Mechanisms of resistance to BTK inhibitors in B cell malignancies and emerging targeted strategies.Molecular therapy. Oncology · 2026Review
- Leveraging Kinase Drugs for Neurosciences: Discovery of Selective, CNS-Penetrant Reversible Bruton's Tyrosine Kinase Inhibitors as Therapeutics for Neuroinflammation.Journal of medicinal chemistry · 2026Article
- When Targeted Therapy Falls Short: Unraveling Resistance Mechanisms in Chronic Lymphocytic Leukemia.Current hematologic malignancy reports · 2026Review
- Resistance to targeted therapies in chronic lymphocytic leukemia: Current status and perspectives for clinical and diagnostic practice.Leukemia · 2025Review
- Resistance mechanisms and approach to chronic lymphocytic leukemia after BTK inhibitor therapy.Leukemia & lymphoma · 2025Review
- Targeting Bruton's tyrosine kinase (BTK) as a signaling pathway in immune-mediated diseases: from molecular mechanisms to leading treatments.Advances in rheumatology (London, England) · 2024Review
- Review
- In BTK, phosphorylated Y223 in the SH3 domain mirrors catalytic activity, but does not influence biological function.Blood advances · 2024Article
- Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL).Genes · 2023Review
- Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance.Blood advances · 2023Article
- BTKbase, Bruton Tyrosine Kinase Variant Database in X-Linked Agammaglobulinemia: Looking Back and Ahead.Human mutation · 2023Article
- Resistance to Bruton tyrosine kinase inhibition in chronic lymphocytic leukaemia and non-Hodgkin lymphoma.British journal of haematology · 2023Review
- Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance.Blood advances · 2022Article
- Crucial Roles of miR-625 in Human Cancer.Frontiers in medicine · 2022Review
- The TKI Era in Chronic Leukemias.Pharmaceutics · 2021Review
- Ibrutinib reduces neutrophil infiltration, preserves neural tissue and enhances locomotor recovery in mouse contusion model of spinal cord injury.Anatomy & cell biology · 2021Article
- The Evolving Landscape of Chronic Lymphocytic Leukemia on Diagnosis, Prognosis and Treatment.Diagnostics (Basel, Switzerland) · 2021Review
- Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Irreversible Bruton tyrosine kinase (BTK) inhibitors, ibrutinib and acalabrutinib have demonstrated remarkable clinical responses in multiple B-cell malignancies. Acquired resistance has been identified in a sub-population of patients in which mutations affecting BTK predominantly substitute cysteine 481 in the kinase domain for catalytically active serine, thereby ablating covalent binding of inhibitors. Activating substitutions in the BTK substrate phospholipase Cγ2 (PLCγ2) instead confers resistance independent of BTK. Herein, we generated all six possible amino acid substitutions due to single nucleotide alterations for the cysteine 481 codon, in addition to threonine, requiring two nucleotide substitutions, and performed functional analysis. Replacement by arginine, phenylalanine, tryptophan or tyrosine completely inactivated the catalytic activity, whereas substitution with glycine caused severe impairment. BTK with threonine replacement was catalytically active, similar to substitution with serine. We identify three potential ibrutinib resistance scenarios for cysteine 481 replacement: (1) Serine, being catalytically active and therefore predominating among patients. (2) Threonine, also being catalytically active, but predicted to be scarce, because two nucleotide changes are needed. (3) As BTK variants replaced with other residues are catalytically inactive, they presumably need compensatory mutations, therefore being very scarce. Glycine and tryptophan variants were not yet reported but likely also provide resistance.
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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.