Mutation in Bruton Tyrosine Kinase (BTK) A428D confers resistance To BTK-degrader therapy in chronic lymphocytic...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Bruton's tyrosine kinase (BTK) inhibitors have revolutionized chronic lymphocytic leukemia (CLL) treatment.
• The development of BTK inhibitors has progressed from covalent to non-covalent forms and now to targeted protein degraders.
• It was presumed that BTK degraders might overcome resistance mechanisms associated with prior BTK inhibitors.

Purpose of the Study:

• To investigate the efficacy of BTK degraders against CLL cells harboring specific BTK mutations.
• To present clinical evidence of resistance to a BTK degrader (BGB-16673) mediated by a BTK kinase domain mutation (A428D).
• To predict potential cross-resistance to other advanced BTK degraders (NX-2127) based on structural modeling.

Main Methods:

• Clinical observation of patient response to BTK degrader therapy.
• Molecular modeling of the BTK A428D mutation within the binding pocket of BTK degraders.
• Analysis of known resistance profiles of BTK mutations to covalent and non-covalent BTK inhibitors.

Main Results:

• Clinical data demonstrate that the BTK A428D mutation confers resistance to the BTK degrader BGB-16673.
• Modeling suggests the A428D mutation, replacing hydrophobic alanine with charged aspartic acid, may hinder binding of NX-2127.
• CLL cells with the BTK A428D mutation are already known to be resistant to covalent and non-covalent BTK inhibitors.

Conclusions:

• The BTK A428D mutation can confer resistance to BTK protein degraders, contrary to initial assumptions.
• The two most advanced BTK degraders in clinical trials (BGB-16673 and NX-2127) may select for CLL cells with BTK A428D.
• This mutation could lead to resistance against all currently developed BTK inhibitors, including degraders, necessitating further therapeutic strategies.