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
Open accessAbstract
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.).
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Integrated analysis of multimodal single-cell data
Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W. M., Zheng, S., Butler, A., Lee, M. J., Wilk, A. J., Darby, C., Zagar, M., et al. (2020) · doi:10.1101/2020.10.12.335331 · Cited by 15,508
UCSF ChimeraX : Structure visualization for researchers, educators, and developers
Pettersen, E. F., Goddard, T. D., Huang, C. C., Meng, E. C., Couch, G. S., Croll, T. I., Morris, J. H., & Ferrin, T. E. (2020) · Protein Science · doi:10.1002/pro.3943 · Cited by 9,521
Simultaneous epitope and transcriptome measurement in single cells
Stoeckius, M., Hafemeister, C., Stephenson, W., Houck-Loomis, B., Chattopadhyay, P. K., Swerdlow, H., Satija, R., & Smibert, P. (2017) · Nature Methods · doi:10.1038/nmeth.4380 · Cited by 3,098
Hallek, M., Cheson, B., Catovsky, D., Caligaris-cappio, F., Dighiero, G., Döhner, H., Hillmen, P., Keating, M., Montserrat, E., Chiorazzi, N., et al. (2018) · Blood · doi:10.1182/blood-2017-09-806398 · Cited by 1,629
Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF
Heidorn, S. J., Milagre, C. S., Whittaker, S. R., Nourry, A., Niculescu‐Duvaz, I., Dhomen, N. S., Hussain, J., Reis-Filho, J. S., Springer, C. J., Pritchard, C. A., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.040 · Cited by 1,497
Resistance Mechanisms for the Bruton's Tyrosine Kinase Inhibitor Ibrutinib
Woyach, J. A., Furman, R. R., Liu, T.-M., Ozer, H. G., Zapatka, M., Ruppert, A. S., Xue, L., Li, D. H.-H., Steggerda, S. M., Versele, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1400029 · Cited by 1,275
Single-Cell Multi-omic Integration Compares and Contrasts Features of Brain Cell Identity
Welch, J. D., Kozareva, V., Ferreira, A., Vanderburg, C., Martin, C., & Macosko, E. Z. (2019) · Cell · doi:10.1016/j.cell.2019.05.006 · Cited by 1,193
Stoeckius, M., Zheng, S., Houck-Loomis, B., Hao, S., Yeung, B. Z., Mauck, W. M., Smibert, P., & Satija, R. (2018) · Genome Biology · doi:10.1186/s13059-018-1603-1 · Cited by 1,046
Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study
Mato, A. R., Shah, N. N., Jurczak, W. J., Cheah, C. Y., Pagel, J. M., Woyach, J. A., Fakhri, B., Eyre, T. A., Lamanna, N., Patel, M. R., et al. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00224-5 · Cited by 486
Self-citationBTK C481S -Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia
Woyach, J. A., Ruppert, A. S., Guinn, D., Lehman, A., Blachly, J. S., Lozanski, A., Heerema, N. A., Zhao, W., Coleman, J., Jones, D., et al. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.70.2282 · Cited by 484
Research works printed but not linked: 1
- 10.1016/j.cell.2021.04.048 · DOI · Paper page
Cited by
Sorted by citations
Diagnosis and Treatment of Chronic Lymphocytic Leukemia
Shadman, M. S. (2023) · JAMA · doi:10.1001/jama.2023.1946 · Cited by 261
Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia
Mato, A. R., Woyach, J. A., Brown, J. R., Ghia, P., Patel, K., Eyre, T. A., Munir, T., Lech‐Marańda, E., Lamanna, N., Tam, C. S. L., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2300696 · Cited by 256
Self-citationKinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127
Montoya, S., Bourcier, J., Noviski, M., Lu, H., Thompson, M. C., Chirino, A., Jahn, J., Sondhi, A. K., Gajewski, S., Tan, Y. S. (., et al. (2024) · Science · doi:10.1126/science.adi5798 · Cited by 175
Self-citationGenomic profiling for clinical decision making in lymphoid neoplasms
de Leval, L., Alizadeh, A. A., Bergsagel, P. L., Campo, E., Davies, A. J., Doǧan, A., Fitzgibbon, J., Horwitz, S. M., Melnick, A. M., Morice, W. G., et al. (2022) · Blood · doi:10.1182/blood.2022015854 · Cited by 176
Self-citationChronic Lymphocytic Leukemia: 2025 Update on the Epidemiology, Pathogenesis, Diagnosis, and Therapy
Hallek, M. J. (2025) · American Journal of Hematology · doi:10.1002/ajh.27546 · Cited by 185
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
- 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 › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
