Reference Detail

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), 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 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 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	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 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	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