Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.
Document Type
Article
Publication Date
2-2-2024
Original Citation
Montoya S,
Bourcier J,
Noviski M,
Lu H,
Thompson M,
Chirino A,
Jahn J,
Sondhi A,
Gajewski S,
Tan Y,
Yung S,
Urban A,
Wang E,
Han C,
Mi X,
Kim W,
Sievers Q,
Auger P,
Bousquet H,
Brathaban N,
Bravo B,
Gessner M,
Guiducci C,
Iuliano J,
Kane T,
Mukerji R,
Reddy P,
Powers J,
Sanchez Garcia de Los Rios M,
Ye J,
Barrientos Risso C,
Tsai D,
Pardo G,
Notti R,
Pardo A,
Affer M,
Nawaratne V,
Totiger T,
Pena-Velasquez C,
Rhodes J,
Zelenetz A,
Alencar A,
Roeker L,
Mehta S,
Garippa R,
Linley A,
Soni R,
Skånland S,
Brown R,
Mato A,
Hansen G,
Abdel-Wahab O,
Taylor J.
Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. Science. 2024;383(6682):eadi5798.
Keywords
JGM, Humans, Agammaglobulinaemia Tyrosine Kinase, Ikaros Transcription Factor, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Phosphorylation, Protein Kinase Inhibitors, Signal Transduction, Proteolysis, Drug Resistance, Neoplasm
JAX Source
Science. 2024;383(6682):eadi5798.
ISSN
1095-9203
PMID
38301010
DOI
https://doi.org/10.1126/science.adi5798
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.