Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.

TitleMechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.
Publication TypeJournal Article
Year of Publication2022
AuthorsWang 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, M Palomba L, Coombs CC, Park JH, Zelenetz A, Roeker L, Rosendahl M, Tsai DE, Ebata K, Brandhuber B, Hyman DM, Aifantis I, Mato A, Taylor J, Abdel-Wahab O
JournalN Engl J Med
Date Published2022 02 24
KeywordsAdenine, Agammaglobulinaemia Tyrosine Kinase, Drug Resistance, Neoplasm, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Middle Aged, Mutation, Phospholipase C gamma, Piperidines, Protein Kinase Inhibitors, Receptors, Antigen, B-Cell, Sequence Analysis, RNA, Signal Transduction

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 (PLCĪ³2), 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 PLCĪ³2 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.).

Alternate JournalN Engl J Med
PubMed ID35196427
Grant ListR01CA216421, R01CA173636, R01CA228135, P01CA229086 / CA / NCI NIH HHS / United States

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