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.).
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.).
Authors: Benjamin H Durham; Bartlomiej Getta; Sascha Dietrich; Justin Taylor; Helen Won; James M Bogenberger; Sasinya Scott; Eunhee Kim; Young Rock Chung; Stephen S Chung; Jennifer Hüllein; Tatjana Walther; Lu Wang; Sydney X Lu; Christopher C Oakes; Raoul Tibes; Torsten Haferlach; Barry S Taylor; Martin S Tallman; Michael F Berger; Jae H Park; Thorsten Zenz; Omar Abdel-Wahab Journal: Blood Date: 2017-08-11 Impact factor: 22.113
Authors: Jennifer A Woyach; Amy S Ruppert; Daphne Guinn; Amy Lehman; James S Blachly; Arletta Lozanski; Nyla A Heerema; Weiqiang Zhao; Joshua Coleman; Daniel Jones; Lynne Abruzzo; Amber Gordon; Rose Mantel; Lisa L Smith; Samantha McWhorter; Melanie Davis; Tzyy-Jye Doong; Fan Ny; Margaret Lucas; Weihong Chase; Jeffrey A Jones; Joseph M Flynn; Kami Maddocks; Kerry Rogers; Samantha Jaglowski; Leslie A Andritsos; Farrukh T Awan; Kristie A Blum; Michael R Grever; Gerard Lozanski; Amy J Johnson; John C Byrd Journal: J Clin Oncol Date: 2017-02-13 Impact factor: 50.717
Authors: Justin Taylor; Xiaoli Mi; Khrystyna North; Moritz Binder; Alexander Penson; Terra Lasho; Katherine Knorr; Michael Haddadin; Bo Liu; Joseph Pangallo; Salima Benbarche; Daniel Wiseman; Ayalew Tefferi; Stephanie Halene; Yang Liang; Mrinal M Patnaik; Robert K Bradley; Omar Abdel-Wahab Journal: Blood Date: 2020-09-24 Impact factor: 25.476