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Ref Type Journal Article
PMID (36183831)
Authors Yuan H, Zhu Y, Cheng Y, Hou J, Jin F, Li M, Jia W, Cheng Z, Xing H, Liu M, Han T
Title BTK kinase activity is dispensable for the survival of diffuse large B-cell lymphoma.
Journal Vol Issue Date Pages Journal Short Title
The Journal of biological chemistry 298 11 2022 Nov 102555 J Biol Chem
URL
Abstract Text Inhibitors targeting Bruton's tyrosine kinase (BTK) have revolutionized the treatment for various B-cell malignancies but are limited by acquired resistance after prolonged treatment as a result of mutations in BTK. Here, by a combination of structural modeling, in vitro assays, and deep phospho-tyrosine proteomics, we demonstrated that four clinically observed BTK mutations-C481F, C481Y, C481R, and L528W-inactivated BTK kinase activity both in vitro and in diffused large B-cell lymphoma (DLBCL) cells. Paradoxically, we found that DLBCL cells harboring kinase-inactive BTK exhibited intact B cell receptor (BCR) signaling, unperturbed transcription, and optimal cellular growth. Moreover, we determined that DLBCL cells with kinase-inactive BTK remained addicted to BCR signaling and were thus sensitive to targeted BTK degradation by the proteolysis-targeting chimera. By performing parallel genome-wide CRISPR-Cas9 screening in DLBCL cells with WT or kinase-inactive BTK, we discovered that DLBCL cells with kinase-inactive BTK displayed increased dependence on Toll-like receptor 9 (TLR9) for their growth and/or survival. Our study demonstrates that the kinase activity of BTK is not essential for oncogenic BCR signaling and suggests that BTK's noncatalytic function is sufficient to sustain the survival of DLBCL.

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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
BTK L528W missense unknown BTK L528W lies within the protein kinase domain of the Btk protein (UniProt.org). L528W confers resistance to BTK inhibitors in culture (PMID: 35196427, PMID: 36183831, PMID: 39728925), results in loss of kinase activity in in vitro assays (PMID: 36183831, PMID: 38301010), increased calcium ion flux and decreased Btk and Plcg2 phosphorylation in culture (PMID: 35196427), but retains downstream signaling (PMID: 35196427) and calcium ion flux similar to wild-type in a different study (PMID: 36183831), 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 C481R diffuse large B-cell lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, diffuse large B-cell lymphoma cell lines expressing BTK C481R demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 36183831). 36183831
BTK L528W diffuse large B-cell lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, diffuse large B-cell lymphoma cell lines expressing BTK L528W demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 36183831). 36183831
BTK C481F diffuse large B-cell lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, diffuse large B-cell lymphoma cell lines expressing BTK C481F demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 36183831). 36183831
BTK C481S diffuse large B-cell lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, diffuse large B-cell lymphoma cell lines expressing BTK C481S demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 36183831). 36183831
BTK C481Y diffuse large B-cell lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, diffuse large B-cell lymphoma cell lines expressing BTK C481Y demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 36183831). 36183831