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Cited by 87Chronic Lymphocytic Leukemia ResearchLymphoma Diagnosis and TreatmentAcute Lymphoblastic Leukemia research

Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance

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Naeem, Aishath, Utro, Filippo, Wang, Qing, Cha, Justin, Vihinen, Mauno, Martindale, Stephen, Zhou, Yinglu, Ren, Yue +17 more·2023·Blood Advances
DOI 10.1182/bloodadvances.2022008447PMC PMC10202739
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Abstract

Covalent inhibitors of Bruton tyrosine kinase (BTK) have transformed the therapy of chronic lymphocytic leukemia (CLL), but continuous therapy has been complicated by the development of resistance. The most common resistance mechanism in patients whose disease progresses on covalent BTK inhibitors (BTKis) is a mutation in the BTK 481 cysteine residue to which the inhibitors bind covalently. Pirtobrutinib is a highly selective, noncovalent BTKi with substantial clinical activity in patients whose disease has progressed on covalent BTKi, regardless of BTK mutation status. Using in vitro ibrutinib-resistant models and cells from patients with CLL, we show that pirtobrutinib potently inhibits BTK-mediated functions including B-cell receptor (BCR) signaling, cell viability, and CCL3/CCL4 chemokine production in both BTK wild-type and C481S mutant CLL cells. We demonstrate that primary CLL cells from responding patients on the pirtobrutinib trial show reduced BCR signaling, cell survival, and CCL3/CCL4 chemokine secretion. At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition, cell viability, and cytokine production. We employed longitudinal whole-exome sequencing on 2 patients whose disease progressed on pirtobrutinib and identified selection of alternative-site BTK mutations, providing clinical evidence that secondary BTK mutations lead to resistance to noncovalent BTKis.

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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 [43]

    The Results section reports adequate kinase activity for T474I and C481S, but essentially no activity for C481R and L528W. The Discussion describes C481F/Y as kinase-dead. Our copy does not establish the classifications given for T474S, M437R, or V416L; the cited passages have no page numbers. (LLM, conf=0.89)

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Research works printed but not linked: 27

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Authors
Naeem, A., Utro, F., Wang, Q., Cha, J., Vihinen, M., Martindale, S., Zhou, Y., Ren, Y., Tyekucheva, S., Kim, A. S., Fernandes, S. M., Saksena, G., Rhrissorrakrai, K., Levovitz, C., Danysh, B. P., Slowik, K., Jacobs, R. A., Davids, M. S., Lederer, J. A., Zain, R., Smith, C. I. E., Leshchiner, I., Parida, L., Getz, G., & Brown, J. R.
Affiliations
  • Broad Institute (US)
  • 3IBM Research, Yorktown Heights, New York, NY
  • Karolinska University Hospital (SE)
  • Lund University (SE)
  • Harvard University (US)
  • Brigham and Women's Hospital (US)
  • 4Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86, Huddinge, Sweden
Corresponding author
Brown, Jennifer R.
ORCID
Venue
Blood Advances
Publisher
American Society of Hematology
Published
2023-05-09
Volume
7
Issue
9
Pages
1929-1943
ISSN
  • 2473-9529 (ISSN-L)
  • 2473-9537
DOI
10.1182/bloodadvances.2022008447
PMC
PMC10202739
OpenAlex
W4307303217
Cited by
87
References
7
Citations by year
2026: 16 · 2025: 29 · 2024: 28 · 2023: 13 · 2022: 1
FWCI
11.03
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Blood Advances (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Ohio State University
  • Cancerfonden
  • Karolinska Institutet
  • National Institutes of Health (HEK293)
  • Loxo Oncology
  • National Cancer Institute (R01CA213442, P50CA206963, P01CA206978)
Topics
  • Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
Keywords
pirtobrutinib, ibrutinib resistance, chronic lymphocytic leukemia, Bruton's tyrosine kinase, BTK C481S mutation, covalent BTK inhibitors, B cell receptor signaling, acquired drug resistance
MeSH terms
Agammaglobulinaemia Tyrosine Kinase, Adenine, Humans, Mutation, Piperidines, Pyrazoles, Pyrimidines, Leukemia, Lymphocytic, Chronic, B-Cell, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Chemokine CCL4

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