Mechanisms of Resistance to Noncovalent Bruton’s Tyrosine Kinase Inhibitors
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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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BTK mutations may be classified as kinase proficient (e.g., T474I/S and C481S) or kinase impaired (e.g., M437R, V416L, C481Y/R/F, and L528W).
“BTKmutations may be classified as kinase proficient (e.g., T474I/S and C481S) or kinase impaired (e.g., M437R, V416L, C481Y/R/F, and L528W) (41–43).”
From Resistance Mechanisms and Approach to Chronic Lymphocytic Leukemia after BTK Inhibitor Therapy (2025) · cites this paper as [42]
The Results section, under “Functional Characterization of Non-C481 BTK Mutants” (page unavailable), reports preserved BTK autophosphorylation for C481S and T474I and reduced catalytic markers for V416L, M437R, and L528W. Our copy does not establish the claimed classifications for T474S or C481Y/R/F. (LLM, conf=0.90)
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- [1]Woyach JA, Ruppert AS, Guinn D, BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol 2017; 35: 1437– 43. 28418267 PMC5455463
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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
- 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
- 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
- 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 › Genetics › 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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