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Ref Type Journal Article
PMID (39048721)
Authors Wong RL, Choi MY, Wang HY, Kipps TJ
Title Mutation in Bruton Tyrosine Kinase (BTK) A428D confers resistance To BTK-degrader therapy in chronic lymphocytic leukemia.
Journal Vol Issue Date Pages Journal Short Title
Leukemia 38 8 2024 Aug 1818-1821 Leukemia
URL
Abstract Text Targeting BTK has profoundly changed the face of CLL treatment over the past decade. 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. However, contrary to the presumption that protein degraders may be impervious to mutations in BTK, we now present clinical evidence that a mutation in the kinase domain of BTK, namely A428D, can confer disease resistance to a BTK degrader currently in clinical trials, that is 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 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BTK T474I chronic lymphocytic leukemia predicted - resistant Pirtobrutinib Case Reports/Case Series Actionable In a clinical case study, a patient with chronic lymphocytic leukemia harboring BTK C481S experienced progressive disease after an initial response on treatment with Jaypirca (pirtobrutinib) and was found to have acquired BTK T474I and lost BTK C481S (PMID: 39048721). 39048721
BTK T474I chronic lymphocytic leukemia predicted - sensitive BGB-16673 Case Reports/Case Series Actionable In a clinical case study, BGB-16673 treatment resulted in reduction in bulky lymphadenopathy in a patient with chronic lymphocytic leukemia harboring BTK T474I (PMID: 39048721). 39048721
BTK A428D chronic lymphocytic leukemia predicted - resistant BGB-16673 Case Reports/Case Series Actionable In a clinical case study, a patient with chronic lymphocytic leukemia harboring BTK T474I experienced progressive disease after an initial response on treatment with BGB-16673 and was found to have acquired BTK A428D and lost BTK T474I (PMID: 39048721). 39048721
BTK C481S chronic lymphocytic leukemia sensitive Pirtobrutinib Case Reports/Case Series Actionable In a clinical case study, Jaypirca (pirtobrutinib) resulted in disease control lasting 7 months in a patient with chronic lymphocytic leukemia harboring BTK C481S (PMID: 39048721). 39048721