Molecular and Structural Basis of Pan-Resistance to BTK Degraders and Inhibitors.
A specific mutation causing resistance to all current BTK drugs has a weakness: cancer cells carrying it struggle to survive without BTK targeting.
Serial sequencing of CLL samples from patients on phase I BTK degrader trials (zelebrudomide and bexobrutideg) revealed recurrent preexisting BTK A428D mutation expansion at relapse, and crystal structure analysis showed the mutant aspartate sterically clashes with ATP and the adenine-mimetic moiety shared by all current BTK inhibitors and degraders. Unlike prior BTK resistance mutations, A428D causes pan-resistance to the entire class, but cells bearing it have a competitive disadvantage off BTK-directed therapy, and venetoclax combination can counteract the selection pressure.
What the study was
- Study design
- translational cohort study with crystallography
- Population
- CLL patients on phase I BTK degrader trials (zelebrudomide, bexobrutideg)
- Category
- Genomics/Precision Medicine
- Maturity
- Validated
- Journal
- Cancer Discovery
Why it surfaced
Identifies the molecular mechanism of the first pan-BTK resistance mutation (A428D) affecting all BTK inhibitors and degraders simultaneously, directly from patients on active trials; provides structural rationale for next-generation BTK therapy design and immediate combination strategy (venetoclax) to suppress resistance.
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