Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.
Science
; 383(6682): eadi5798, 2024 Feb 02.
Article
in En
| MEDLINE
| ID: mdl-38301010
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukemia, Lymphocytic, Chronic, B-Cell
/
Drug Resistance, Neoplasm
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Protein Kinase Inhibitors
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Ikaros Transcription Factor
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Proteolysis
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Agammaglobulinaemia Tyrosine Kinase
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Sci. (N.Y., N.Y.)
/
Science
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: