Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant

Hamasy, A; Wang, Q; Blomberg, K E M; Mohammad, D K; Yu, L; Vihinen, M; Berglöf, A; Smith, C I E

doi:10.1038/leu.2016.153

Cited by 65Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentLung Cancer Treatments and Mutations

Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant

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Hamasy, A, Wang, Q, Blomberg, K E M, Mohammad, D K, Yu, L, Vihinen, M, Berglöf, A, Smith, C I E·2017·Leukemia

DOI 10.1038/leu.2016.153PMC PMC5220130

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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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Most BTK mutations are single base pair substitutions affecting C481.
“Most BTK mutations are single base pair substitutions affecting C481(Figure 3) (12, 34).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [34]
The Introduction says single-nucleotide changes at the C481 codon are the most frequent mutational event in the paper’s discussion of acquired ibrutinib resistance. It does not say that most BTK mutations overall affect C481; the Discussion describes BTK mutations elsewhere, including hotspots at arginine residues. No page number is available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
In contrast to C481S, which retains the enzymatic activity of BTK, C481Y/R/F cause steric hindrance and structural clashing within the ATP binding pocket, preventing BTK Y223 autophosphorylation.
“In contrast to C481S, which retains the enzymatic activity of BTK, C481Y/R/F cause steric hindrance and structural clashing within the ATP binding pocket, preventing BTK Y223 autophosphorylation (34, 37).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [34]
The Results sections on differential catalytic activity and structure–function correlation (pages not provided) support retained activity for C481S, severely compromised Y223 phosphorylation for C481F/R/Y, and structural clashes for the bulky F and Y substitutions. They do not support the proposed mechanism for C481R: the paper says its flexible side chain can be accommodated in the structure, rather than causing a structural clash. (LLM, conf=0.88)
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“Most BTK mutations are single base pair substitutions affecting c481 (Figure 2) [12,33]. the first reported BTK mutation in cll patients with progressive disease on ibrutinib [19,34] was a missense mutation changing c481 to serine (c481S) [19]. the c481S mutation disrupts the covalent binding of…”
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BindingDB Entry 50016318: Medicinal Chemistry Strategies for the Development of Bruton's Tyrosine Kinase Inhibitors against Resistance.
BindingDB (2023) · UC San Diego · doi:10.7270/q2fx7fhq
BindingDB Entry 50012621: Design, synthesis and biological evaluation of 7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as selective Btk inhibitors with improved pharmacokinetic properties for the treatment of rheumatoid arthritis.
BindingDB (2022) · UC San Diego · doi:10.7270/q2p272tr
BindingDB Entry 50008045: Discovery and structure-activity relationship of novel diphenylthiazole derivatives as BTK inhibitor with potent activity against B cell lymphoma cell lines.
BindingDB (2021) · UC San Diego · doi:10.7270/q2pn98zn
BindingDB Entry 50022072: Targeting Solvent-Front Mutations for Kinase Drug Discovery: From Structural Basis to Design Strategies.
BindingDB (2025) · UC San Diego · doi:10.7270/q21n85tb

Evaluating ibrutinib, pirtobrutinib, remibrutinib, rilzabrutinib, and zanubrutinib in 34 BTK-variants at 7 inhibitor resistance sitesPreprint
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Combination of Gatekeeper Mutations and Cysteine 481 Replacement Causes Super Resistance to the Irreversible BTK Inhibitors Ibrutinib, Acalabrutinib and Zanubrutinib
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BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib
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KINASE‐DEAD BRUTON’S TYROSINE KINASE (BTK) C481F/Y MUTANTS CONFER IBRUTINIB RESISTANCE THROUGH ACTIVATION OF HEMATOPOIETIC CELL KINASE (HCK)
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Authors: Hamasy, A., Wang, Q., Blomberg, K. E. M., Mohammad, D. K., Yu, L., Vihinen, M., Berglöf, A., & Smith, C. I. E.
Affiliations: Karolinska University Hospital (SE)
Lund University (SE)
Corresponding author: Hamasy, A
Smith, C I E
ORCID: Wang, Q
Vihinen, M
Berglöf, A
Venue: Leukemia
Publisher: Springer Science and Business Media LLC
Published: 2016-05-25
Volume: 31
Issue: 1
Pages: 177-185
ISSN: 0887-6924 (ISSN-L)
1476-5551
DOI: 10.1038/leu.2016.153
PMC: PMC5220130
OpenAlex: W2413032717
Cited by: 62
References: 71
Citations by year: 2026: 6 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 8 · 2021: 8 · 2020: 6 · 2019: 6 · 2018: 7 · 2017: 5 · 2016: 2
FWCI: 4.84
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0 (tdm)
Locations: Leukemia (publishedVersion, cc-by-nc-sa)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
Funders: Cancerfonden (CAN2013/389)
Medical Research Council
Topics: Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: Bruton's tyrosine kinase, ibrutinib resistance, acalabrutinib, kinase activity, PLCγ2, B-cell malignancies, point mutations, compensatory mutations
MeSH terms: Agammaglobulinaemia Tyrosine Kinase, Adenine, Animals, Cell Line, Cysteine, Humans, Piperidines, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidines, Threonine, Transfection, Drug Resistance, Neoplasm, Amino Acid Substitution, Protein Kinase Inhibitors, Biocatalysis

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant

Abstract

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