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

The DOI matches its Crossref record; 22 of the 22 references it cites were found in a registry or an index.

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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Metadata

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
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
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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