Targeting Bruton's Tyrosine Kinase (BTK) has profoundly changed the face of treatment for patients with chronic lymphocytic leukemia (CLL). Iterative advances in the cat and mouse game of resistance and redesign have moved BTK inhibitors from covalent to non-covalent and now targeted protein degraders.
In the journal Leukemia 38:1818 (2024), Kipps and colleagues describe a patient who developed successive resistance to a covalent BTKi, then a non-covalent BTKi, and then a BTK-degrader through acquisition of distinctive mutations in BTK. Each mutation in BTK depicted in red font in the figure conferred resistance to the ongoing BTKi therapy, as indicated on the top of the figure. Each BTK mutation was identified in isolation of the others, originating from the same base ‘mother clone’ of CLL that harbored del(17p), mutation in TP53 (G244S), and complex karyotype. The TP53 mutation (G244S) encodes a mutant TP53 protein that is unable to induce expression of CDKN1A. This apparently allows for unchecked proliferation of each mutant subclone when it becomes immune from the ongoing BTKi therapy, resulting in disease progression on each type of BTKi therapy, including a BTK-degrader.
This case also illustrates that a mutation in the kinase domain of BTK, namely A428D, can confer disease resistance to a BTK degrader, namely BGB-16673. Modeling of a BTK A428D mutation places a negatively charged aspartic acid in place of the hydrophobic side chain of alanine within the binding pocket of another BTK-degrader also in clinical development, namely NX-2127, suggesting that CLL cells with BTK A428D also may be resistant to NX-2127, as they already are known to be with either non-covalent or covalent inhibitors of BTK. Consequently, the two BTK degraders furthest advanced in clinical trials potentially may select for CLL cells with BTK A428D that are resistant to all approved BTKi’s.
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