Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors

Eric Wang, Xiaoli Mi, Meghan C. Thompson, Skye Montoya, Ryan Q. Notti, Jumana Afaghani, Benjamin H. Durham, Alex Penson, Matthew T. Witkowski, Sydney X. Lu, Jessie Bourcier, Simon J. Hogg, Caroline Erickson, Dan Cui, Hana Cho, Michael Singer, Tulasigeri M. Totiger, Sana Chaudhry, Mark Geyer, Alvaro AlencarAdam J. Linley, M. Lia Palomba, Catherine C. Coombs, Jae H. Park, Andrew Zelenetz, Lindsey Roeker, Mary Rosendahl, Donald E. Tsai, Kevin Ebata, Barbara Brandhuber, David M. Hyman, Iannis Aifantis, Anthony Mato, Justin Taylor, Omar Abdel-Wahab

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)735-743
Number of pages9
JournalNew England Journal of Medicine
Volume386
Issue number8
DOIs
StatePublished - Feb 24 2022
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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