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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors
Quinlan Sievers1, Hao Lu2, Allison Cool3
1Memorial Sloan Kettering Cancer Center New York, NY United States.
Abstract:
Early-phase clinical trials of Bruton's tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate clashes with the adenine ring of ATP and the adenine-mimetic moiety of BTK inhibitors and degraders. Combining BTK degraders with venetoclax mitigated the expansion of BTK A428D. These results provide the molecular basis for clinical resistance to BTK degraders and will inform the development of next-generation BTK degrader therapies.
Insights
A new mutation, Bruton
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bruton's tyrosine kinase (BTK) inhibitors are effective for chronic lymphocytic leukemia (CLL).
- Resistance to BTK inhibitors is a clinical challenge.
- BTK degraders show promise but resistance mechanisms are unclear.
Purpose of the Study:
- To investigate the molecular mechanisms of clinical resistance to BTK degraders in CLL.
- To identify novel mutations conferring resistance to BTK degraders.
Main Methods:
- Whole-exome sequencing of serial CLL samples from patients treated with BTK degraders.
- Functional assays to assess the impact of mutations on BTK activity and drug sensitivity.
- X-ray crystallography to determine the structural basis of resistance.
Main Results:
- Recurrent BTK A428D mutation identified at relapse in patients treated with BTK degraders.
- BTK A428D confers resistance to both BTK inhibitors and degraders.
- Structural analysis reveals steric clash of A428D with ATP and BTK-targeted drugs.
- BTK A428D-mutated cells have a competitive disadvantage without BTK-directed therapy.
- Combination therapy with venetoclax mitigated expansion of BTK A428D.
Conclusions:
- BTK A428D is a novel pan-resistance mutation to BTK inhibitors and degraders.
- Understanding this resistance mechanism is crucial for developing next-generation BTK-targeted therapies.
- Combination strategies may overcome resistance to BTK degraders.
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