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Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors

Wang, E, Mi, X, Thompson, MC, Montoya, S, Notti, RQ, Afaghani, J, Durham, BH, Penson, A, Witkowski, MT, Lu, SX, Bourcier, J, Hogg, SJ, Erickson, C, Cui, D, Cho, H, Singer, M, Totiger, TM, Chaudhry, S, Geyer, M, Alencar, A , Linley, AJ, Palomba, ML, Coombs, CC, Park, JH, Zelenetz, A, Roeker, L, Rosendahl, M, Tsai, DE, Ebata, K, Brandhuber, B, Hyman, DM, Aifantis, I, Mato, A, Taylor, J and Abdel-Wahab, O (2022) Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors. The New England journal of medicine, 386 (8). pp. 735-743. ISSN 0028-4793

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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.)

Item Type: Article
Additional Information: From The New England journal of medicine,The Author(s), Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors ,Volume No 386, Page No 8. Copyright © 2022 Massachusetts Medical Society. Reprinted with permission. http://doi.org/10.1056/nejmoa2114110
Uncontrolled Keywords: Humans; Piperidines; Adenine; Receptors, Antigen, B-Cell; Protein Kinase Inhibitors; Sequence Analysis, RNA; Signal Transduction; Drug Resistance, Neoplasm; Mutation; Middle Aged; Phospholipase C gamma; Leukemia, Lymphocytic, Chronic, B-Cell; Agammaglobulinaemia Tyrosine Kinase; Humans; Middle Aged; Adenine; Agammaglobulinaemia Tyrosine Kinase; Drug Resistance, Neoplasm; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Phospholipase C gamma; Piperidines; Protein Kinase Inhibitors; Receptors, Antigen, B-Cell; Sequence Analysis, RNA; Signal Transduction; 11 Medical and Health Sciences; General & Internal Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Massachusetts Medical Society
SWORD Depositor: A Symplectic
Date Deposited: 10 Jul 2023 15:20
Last Modified: 01 Aug 2023 10:55
DOI or ID number: 10.1056/nejmoa2114110
URI: https://researchonline.ljmu.ac.uk/id/eprint/20308
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