Wang, E, Mi, X, Thompson, MC, Montoya, S, Notti, RQ, Afaghani, J, Durham, BH, Penson, A, Witkowski, MT, Lu, SX et al (show 25 more authors)
(2022)
Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors
New England Journal of Medicine, 386 (8).
pp. 735-743.
ISSN 0028-4793, 1533-4406
|
PDF
Wang et al 2022 NEJM.pdf - Published version Download (908kB) | Preview |
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.
| Item Type: | Article |
|---|---|
| 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 |
| Divisions: | Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 24 Nov 2022 14:14 |
| Last Modified: | 21 Jan 2026 17:39 |
| DOI: | 10.1056/NEJMoa2114110 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3166359 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
Altmetric
Altmetric