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Ref Type Journal Article
PMID (27282255)
Authors Hamasy A, Wang Q, Blomberg KE, Mohammad DK, Yu L, Vihinen M, Berglöf A, Smith CI
Title Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant.
Journal Vol Issue Date Pages Journal Short Title
Leukemia 31 1 2017 Jan 177-185 Leukemia
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BTK C481F missense unknown BTK C481F lies within the protein kinase domain of the Btk protein (UniProt.org). C481F confers resistance to BTK inhibitors (PMID: 25189416, PMID: 28178345, PMID: 27282255, PMID: 35639855) and results in loss of autophosphorylation (PMID: 25189416, PMID: 28178345, PMID: 27282255) and loss of kinase activity in an in vitro assay (PMID: 36183831), but maintains BCR signaling through activation of Hck in culture (PMID: 35639855), and therefore, its effect on Btk protein function is unknown. Y
BTK C481R missense loss of function BTK C481R lies within the protein kinase domain of the Btk protein (UniProt.org). C481R confers a loss of function to the Btk protein as indicated by altered enzymatic activity in an in vitro assay (PMID: 27571029), decreased kinase activity in culture (PMID: 27282255), and decreased autophosphorylation and downstream signaling in culture (PMID: 27282255).
BTK C481S missense no effect BTK C481S lies within the protein kinase domain of the Btk protein (UniProt.org). C481S demonstrates kinase activity similar to wild-type Btk (PMID: 38301010), but confers Imbruvica (ibrutinib) resistance in cell culture (PMID: 27282255, PMID: 28573668) through interference of drug binding (PMID: 25189416, PMID: 23940282). Y
BTK C481T missense no effect BTK C481T lies within the protein kinase domain of the Btk protein (UniProt.org). C481T demonstrates kinase activity similar to wild-type Btk, but confers Imbruvica (ibrutinib) resistance in cell culture (PMID: 27282255). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BTK C481T lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, lymphoma cells over expressing BTK C481T were resistant to Imbruvica (ibrutinib) in culture (PMID: 27282255). 27282255
BTK C481T Advanced Solid Tumor resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing BTK C481T were resistant to Imbruvica (ibrutinib) in culture (PMID: 27282255). 27282255