1. Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.
- Author
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Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, Chirino A, Jahn J, Sondhi AK, Gajewski S, Tan YSM, Yung S, Urban A, Wang E, Han C, Mi X, Kim WJ, Sievers Q, Auger P, Bousquet H, Brathaban N, Bravo B, Gessner M, Guiducci C, Iuliano JN, Kane T, Mukerji R, Reddy PJ, Powers J, Sanchez Garcia de Los Rios M, Ye J, Barrientos Risso C, Tsai D, Pardo G, Notti RQ, Pardo A, Affer M, Nawaratne V, Totiger TM, Pena-Velasquez C, Rhodes JM, Zelenetz AD, Alencar A, Roeker LE, Mehta S, Garippa R, Linley A, Soni RK, Skånland SS, Brown RJ, Mato AR, Hansen GM, Abdel-Wahab O, and Taylor J
- Subjects
- Humans, Mutation, Phosphorylation, Signal Transduction, Agammaglobulinaemia Tyrosine Kinase genetics, Agammaglobulinaemia Tyrosine Kinase metabolism, Ikaros Transcription Factor metabolism, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Proteolysis drug effects, Drug Resistance, Neoplasm drug effects
- Abstract
Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.
- Published
- 2024
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