PHOSPHOLIPASE C GAMMA 2 AND RESISTANCE ASSOCIATED MUTATIONS

摘要

Described herein is a mutation that confers resistance to the treatment with a BTK inhibitor. Described herein is a modified PLCγ2 polypeptide that is modified at amino acid position 742, 845, or 1140 and the modified PLCγ2 polypeptide exhibits decreased inhibition (e.g., resistance) to a covalent and/or irreversible BTK inhibitor. Described herein are diagnostic methods for detecting the modified polypeptide and nucleic acid encoding the modified polypeptide and applications of the methods thereof. Described herein are compositions, combinations, and kits containing the modified polypeptide and methods of using the modified polypeptide. Also described herein are methods of using the modified polypeptide as screening agents for the identification and design of inhibitors of PLCγ2.

主权项

1. A method of assessing whether a subject having a hematologic cancer is less responsive or likely to become less responsive to therapy with a BTK inhibitor, comprising:
a. testing a sample containing a nucleic acid molecule encoding a PLCγ2 polypeptide from the subject; b. determining whether the encoded PLCγ2 polypeptide is modified at an amino acid position corresponding to amino acid position 742, 845, or 1140 of the amino acid sequence set forth in SEQ ID NO: 2; and c. characterizing the subject as resistant or likely to become resistant to therapy with a BTK inhibitor if the subject has the modification at amino acid position 742, 845, or 1140.