Cited by 272Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentLung Cancer Treatments and Mutations

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Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors

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Wang, Eric, Mi, Xiaoli, Thompson, Meghan C., Montoya, Skye, Notti, Ryan Q., Afaghani, Jumana, Durham, Benjamin H., Penson, Alex, Witkowski, Matthew T., Lu, Sydney X., Bourcier, Jessie, Hogg, Simon J., Erickson, Caroline, Cui, Dan, Cho, Hana, Singer, Michael, Totiger, Tulasigeri M., Chaudhry, Sana, Geyer, Mark, Alencar, Alvaro, Linley, Adam J., Palomba, M. Lia, Coombs, Catherine C., Park, Jae H., Zelenetz, Andrew, Roeker, Lindsey, Rosendahl, Mary, Tsai, Donald E., Ebata, Kevin, Brandhuber, Barbara, Hyman, David M., Aifantis, Iannis, Mato, Anthony, Taylor, Justin, Abdel-Wahab, Omar·2022·New England Journal of Medicine

DOI 10.1056/nejmoa2114110PMC PMC9074143

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Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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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Self-citation
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Self-citation

Authors: Wang, E., Mi, X., Thompson, M. C., Montoya, S., Notti, R. Q., Afaghani, J., Durham, B. H., Penson, A., Witkowski, M. T., Lu, S. X., Bourcier, J., Hogg, S. J., Erickson, C., Cui, D., Cho, H., Singer, M., Totiger, T. M., Chaudhry, S., Geyer, M., Alencar, A., Linley, A. J., Palomba, M. L., Coombs, C. C., Park, J. H., Zelenetz, A., Roeker, L., Rosendahl, M., Tsai, D. E., Ebata, K., Brandhuber, B., Hyman, D. M., Aifantis, I., Mato, A., Taylor, J., & Abdel-Wahab, O.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
ORCID: Montoya, Skye
Notti, Ryan Q.
Lu, Sydney X.
Bourcier, Jessie
Alencar, Alvaro
Linley, Adam J.
Zelenetz, Andrew
Roeker, Lindsey
Ebata, Kevin
Taylor, Justin
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2022-02-24
Volume: 386
Issue: 8
Pages: 735-743
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa2114110
PMC: PMC9074143
OpenAlex: W4213416073
Cited by: 272
References: 22
Citations by year: 2026: 49 · 2025: 70 · 2024: 73 · 2023: 55 · 2022: 25
FWCI: 34.64
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Liverpool John Moores University (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: Lymphoma Research Foundation
CLL Society
LOXO Oncology
Leukemia and Lymphoma Society
Doris Duke Charitable Foundation
National Cancer Institute (R01CA216421, R01CA173636, R01CA228135, P01CA229086)
American Society of Hematology
Robert Wood Johnson Foundation
Edward P. Evans Foundation
Society of Memorial Sloan Kettering
Lymphoma Foundation
Topics: Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: Bruton's tyrosine kinase, BTK inhibitors, pirtobrutinib, drug resistance, chronic lymphocytic leukemia, BTK mutations, non-covalent inhibitors, covalent BTK inhibitors, B cell receptor signaling, kinase domain mutations, acquired resistance
MeSH terms: Agammaglobulinaemia Tyrosine Kinase, Adenine, Humans, Middle Aged, Mutation, Piperidines, Pyrazoles, Receptors, Antigen, B-Cell, Signal Transduction, Leukemia, Lymphocytic, Chronic, B-Cell, Sequence Analysis, RNA, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Phospholipase C gamma

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Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors

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