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Ref Type Journal Article
PMID (35196427)
Authors Wang E, Mi X, Thompson MC, Montoya S, Notti RQ, Afaghani J, Durham BH, Penson A, Witkowski MT, Lu SX, Bourcier J, Hogg SJ, Erickson C, Cui D, Cho H, Singer M, Totiger TM, Chaudhry S, Geyer M, Alencar A, Linley AJ, Palomba ML, Coombs CC, Park JH, Zelenetz A, Roeker L, Rosendahl M, Tsai DE, Ebata K, Brandhuber B, Hyman DM, Aifantis I, Mato A, Taylor J, Abdel-Wahab O
Title Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.
Journal Vol Issue Date Pages Journal Short Title
The New England journal of medicine 386 8 2022 02 24 735-743 N Engl J Med
URL
Abstract Text Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood.We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors.Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors.Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.).

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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 A428D missense unknown BTK A428D lies within the protein kinase domain of the Btk protein (UniProt.org). A428D results in decreased Btk and Plcg2 phosphorylation and increased calcium ion flux but retains Akt and Erk phosphorylation and demonstrates resistance to BTK inhibitors in culture (PMID: 35196427), 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
BTK M437R missense unknown BTK M437R lies within the protein kinase domain of the Btk protein (UniProt.org). M437R retains Akt and Erk phosphorylation, but results in increased calcium ion flux, decreased Btk and Plcg2 phosphorylation in culture (PMID: 35196427), and decreased kinase activity in an in vitro assay (PMID: 38301010), and demonstrates resistance to BTK inhibitors in culture (PMID: 35196427), and therefore, its effect on Btk protein function is unknown. Y
BTK V416L missense loss of function - predicted BTK V416L lies within the protein kinase domain of the Btk protein (UniProt.org). V416L retains Akt and Erk phosphorylation in culture (PMID: 35196427, PMID: 36661329), but results in decreased Btk autophosphorylation and loss of kinase activity in culture (PMID: 38301010), decreased Btk and Plcg2 phosphorylation and increased calcium ion flux in culture, and demonstrates resistance to BTK inhibitors in culture (PMID: 35196427, PMID: 36661329), and therefore, is predicted to lead to a loss of Btk protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BTK A428D diffuse large B-cell lymphoma resistant Pirtobrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK A428D demonstrated resistance to Jaypirca (pirtobrutinib) in culture (PMID: 35196427). 35196427
BTK V416L diffuse large B-cell lymphoma resistant Fenebrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK V416L demonstrated resistance to Fenebrutinib (GDC-0853) in culture (PMID: 35196427). 35196427
BTK T474I BTK L528W chronic lymphocytic leukemia predicted - resistant Pirtobrutinib Case Reports/Case Series Actionable In a clinical case study, a patient with chronic lymphocytic leukemia harboring BTK C481S who previously responded to Jaypirca (pirtobrutinib) treatment was found to have acquired BTK T474I and BTK L528W upon disease progression (PMID: 35196427). 35196427
BTK V416L diffuse large B-cell lymphoma resistant Vecabrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK V416L demonstrated resistance to Vecabrutinib (SNS-062) in culture (PMID: 35196427). 35196427
BTK M437R chronic lymphocytic leukemia predicted - resistant Pirtobrutinib Case Reports/Case Series Actionable In a clinical case study, a patient with chronic lymphocytic leukemia harboring BTK C481S who previously responded to Jaypirca (pirtobrutinib) treatment was found to have acquired BTK M437R upon disease progression (PMID: 35196427). 35196427
BTK L528W diffuse large B-cell lymphoma resistant Fenebrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK L528W demonstrated resistance to Fenebrutinib (GDC-0853) in culture (PMID: 35196427). 35196427
BTK A428D diffuse large B-cell lymphoma resistant Vecabrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK A428D demonstrated resistance to Vecabrutinib (SNS-062) in culture (PMID: 35196427). 35196427
BTK T474I diffuse large B-cell lymphoma sensitive Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, Imbruvica (ibrutinib) treatment inhibited phosphorylation of Btk and decreased viability of a diffuse large B-cell lymphoma cell line expressing BTK T474I in culture (PMID: 35196427). 35196427
BTK C481S diffuse large B-cell lymphoma sensitive Vecabrutinib Preclinical - Cell culture Actionable In a preclinical study, Vecabrutinib (SNS-062) treatment inhibited viability of a diffuse large B-cell lymphoma cell line harboring BTK C481S in culture (PMID: 35196427). 35196427
BTK V416L chronic lymphocytic leukemia predicted - resistant Pirtobrutinib Case Reports/Case Series Actionable In a clinical case study, a patient with chronic lymphocytic leukemia who previously responded to Jaypirca (pirtobrutinib) treatment was found to have acquired a BTK V416L upon disease progression (PMID: 35196427). 35196427
BTK C481S diffuse large B-cell lymphoma sensitive Pirtobrutinib Preclinical - Cell culture Actionable In a preclinical study, Jaypirca (pirtobrutinib) treatment inhibited viability of a diffuse large B-cell lymphoma cell line harboring BTK C481S in culture (PMID: 35196427). 35196427
BTK M437R diffuse large B-cell lymphoma resistant Pirtobrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK M437R demonstrated resistance to Jaypirca (pirtobrutinib) in culture (PMID: 35196427). 35196427
BTK T474I diffuse large B-cell lymphoma resistant Vecabrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK T474I demonstrated resistance to Vecabrutinib (SNS-062) in culture (PMID: 35196427). 35196427
BTK T474I chronic lymphocytic leukemia predicted - resistant Pirtobrutinib Case Reports/Case Series Actionable In a clinical case study, two patients with chronic lymphocytic leukemia who previously responded to Jaypirca (pirtobrutinib) treatment were found to have acquired BTK T474I upon disease progression (PMID: 35196427). 35196427
BTK C481S diffuse large B-cell lymphoma sensitive Fenebrutinib Preclinical - Cell culture Actionable In a preclinical study, Fenebrutinib (GDC-0853) treatment inhibited viability of a diffuse large B-cell lymphoma cell line harboring BTK C481S in culture (PMID: 35196427). 35196427
BTK M437R diffuse large B-cell lymphoma resistant Fenebrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK M437R demonstrated resistance to Fenebrutinib (GDC-0853) in culture (PMID: 35196427). 35196427
BTK M437R diffuse large B-cell lymphoma sensitive ARQ 531 Preclinical - Cell culture Actionable In a preclinical study, ARQ 531 treatment inhibited viability of a diffuse large B-cell lymphoma cell line harboring BTK M437R in culture (PMID: 35196427). 35196427
BTK C481S diffuse large B-cell lymphoma sensitive ARQ 531 Preclinical - Cell culture Actionable In a preclinical study, ARQ 531 treatment inhibited viability of a diffuse large B-cell lymphoma cell line harboring BTK C481S in culture (PMID: 35196427). 35196427
BTK V416L diffuse large B-cell lymphoma sensitive Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, Imbruvica (ibrutinib) treatment inhibited phosphorylation of Btk and decreased viability of a diffuse large B-cell lymphoma cell line expressing BTK V416L in culture (PMID: 35196427). 35196427
BTK M437R diffuse large B-cell lymphoma sensitive Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, Imbruvica (ibrutinib) treatment inhibited phosphorylation of Btk and decreased viability of a diffuse large B-cell lymphoma cell line expressing BTK M437R in culture (PMID: 35196427). 35196427
BTK A428D diffuse large B-cell lymphoma resistant Fenebrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK A428D demonstrated resistance to Fenebrutinib (GDC-0853) in culture (PMID: 35196427). 35196427
BTK T474I diffuse large B-cell lymphoma resistant Fenebrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK T474I demonstrated resistance to Fenebrutinib (GDC-0853) in culture (PMID: 35196427). 35196427
BTK A428D diffuse large B-cell lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK A428D demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 35196427). 35196427
BTK V416L diffuse large B-cell lymphoma resistant Pirtobrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK V416L demonstrated resistance to Jaypirca (pirtobrutinib) in culture (PMID: 35196427). 35196427
BTK L528W diffuse large B-cell lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK L528W demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 35196427). 35196427
BTK V416L diffuse large B-cell lymphoma sensitive ARQ 531 Preclinical - Cell culture Actionable In a preclinical study, ARQ 531 treatment inhibited viability of a diffuse large B-cell lymphoma cell line harboring BTK V416L in culture (PMID: 35196427). 35196427
BTK L528W diffuse large B-cell lymphoma resistant Vecabrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK L528W demonstrated resistance to Vecabrutinib (SNS-062) in culture (PMID: 35196427). 35196427
BTK L528W diffuse large B-cell lymphoma resistant Pirtobrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK L528W demonstrated resistance to Jaypirca (pirtobrutinib) in culture (PMID: 35196427). 35196427
BTK C481S diffuse large B-cell lymphoma resistant Ibrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK C481S demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 35196427). 35196427
BTK L528W chronic lymphocytic leukemia predicted - resistant Pirtobrutinib Case Reports/Case Series Actionable In a clinical case study, 2 patients with chronic lymphocytic leukemia who previously responded to Jaypirca (pirtobrutinib) treatment were found to have acquired BTK L528W upon disease progression (PMID: 35196427). 35196427
BTK T474I diffuse large B-cell lymphoma resistant Pirtobrutinib Preclinical - Cell culture Actionable In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK T474I demonstrated resistance to Jaypirca (pirtobrutinib) in culture (PMID: 35196427). 35196427