MUTATIONS ASSOCIATED WITH RESISTANCE TO INHIBITORS OF BRUTON'S TYROSINE KINASE (BTK)

摘要

Described herein are mutations that confer resistance to treatment with a BTK inhibitor. Described herein are modified BTK polypeptides that exhibit decreased inhibition (i.e. are resistant) to a covalent and/or irreversible BTK inhibitor. Also described herein modifications of PLCy2 and CARD 11 polypeptides that confer resistance to treatment with a BTK inhibitor. Described herein are diagnostic methods for detecting the modified polypeptides and nucleic acids encoding the modified polypeptides and applications of the methods thereof. Described herein are compositions, combinations, and kits containing the modified polypeptides and methods of using the modified polypeptides. Also described herein are methods of using modified BTK polypeptides as screening agents for the identification and design of second-generation BTK inhibitors.

主权项

1. A method for determining whether a subject is or likely to become less responsive to therapy with a covalent and/or irreversible Bruton's Tyrosine Kinase (BTK) inhibitor, comprising:
(a) testing a sample containing a nucleic acid molecule encoding a BTK polypeptide from the subject to determine whether the encoded BTK polypeptide is modified at an amino acid position corresponding to amino acid position 481 of the amino acid sequence set forth in SEQ ID NO: 1; and (b) characterizing the subject as resistant or likely to become resistant to therapy with a covalent and/or irreversible BTK inhibitor if the subject has the modification.