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Ref Type Journal Article
PMID (35639855)
Authors Dhami K, Chakraborty A, Gururaja TL, Cheung LW, Sun C, DeAnda F, Huang X
Title Kinase-deficient BTK mutants confer ibrutinib resistance through activation of the kinase HCK.
Journal Vol Issue Date Pages Journal Short Title
Science signaling 15 736 2022 May 31 eabg5216 Sci Signal
URL
Abstract Text The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib irreversibly binds BTK at Cys481, inhibiting its kinase activity and thus blocking transduction of B cell receptor (BCR) signaling. Although ibrutinib is durably effective in patients with B cell malignancies, many patients still develop ibrutinib-resistant disease. Resistance can arise because of mutations at the ibrutinib-binding site in BTK. Here, we characterized the mechanism by which two BTK mutations, C481F and C481Y, may lead to ibrutinib resistance. Both mutants lacked detectable kinase activity in in vitro kinase assays. Structural modeling suggested that bulky Phe and Tyr side chains at position 481 sterically hinder access to the ATP-binding pocket in BTK, contributing to loss of kinase activity. Nonetheless, BCR signaling still propagated through BTK C481F and C481Y mutants to downstream effectors, the phospholipase PLCγ2 and the transcription factor NF-κB. This maintenance of BCR signaling was partially achieved through the physical recruitment and kinase-independent activation of hematopoietic cell kinase (HCK). Upon BCR activation, BTK C481F or C481Y was phosphorylated by Src family kinases at Tyr551, which then bound to the SH2 domain of HCK. Modeling suggested that this binding disrupted an intramolecular autoinhibitory interaction in HCK. Activated HCK subsequently phosphorylated PLCγ2, which propagated BCR signaling and promoted clonogenic cell proliferation. This kinase-independent mechanism could inform therapeutic approaches to CLL bearing either the C481F or C481Y BTK mutants.

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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 C481Y missense unknown BTK C481Y lies within the protein kinase domain of the Btk protein (UniProt.org). C481Y confers resistance to BTK inhibitors, results in a loss of Btk kinase activity in in vitro assays and in cell culture (PMID: 36183831, PMID: 35639855), but maintains BCR signaling through activation of Hck in culture (PMID: 35639855), and therefore, its effect on Btk protein function is unknown. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BTK C481F hematologic cancer resistant Zanubrutinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing BTK C481F were resistant to treatment with Brukinsa (zanubrutinib) in culture (PMID: 35639855). 35639855
BTK C481Y hematologic cancer sensitive A-419259 Preclinical - Cell culture Actionable In a preclinical study, A-419259 inhibited colony formation in an Imbruvica (ibrutinib)-resistant cell line harboring BTK C481Y in culture (PMID: 35639855). 35639855
BTK C481F hematologic cancer resistant Acalabrutinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing BTK C481F were resistant to treatment with Calquence (acalabrutinib) in culture (PMID: 35639855). 35639855
BTK C481Y hematologic cancer resistant Acalabrutinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing BTK C481Y were resistant to treatment with Calquence (acalabrutinib) in culture (PMID: 35639855). 35639855
BTK C481F hematologic cancer resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, cells expressing BTK C481F were resistant to treatment with Imbruvica (ibrutinib) in culture (PMID: 35639855). 35639855
BTK C481Y hematologic cancer resistant Zanubrutinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing BTK C481Y were resistant to treatment with Brukinsa (zanubrutinib) in culture (PMID: 35639855). 35639855