作者
Skye Montoya,Jessie Bourcier,Mark Noviski,Hao Lu,Meghan C. Thompson,Alexandra Chirino,Jacob Jahn,Anya K. Sondhi,Stefan Gajewski,Yuping Tan,Stephanie Yung,Aleksandra Urban,Eric Wang,Cuijuan Han,Xiaoli Mi,Won Jun Kim,Quinlan L. Sievers,P. Auger,Hugo Bousquet,Nivetha Brathaban,Brandon Bravo,Melissa Gessner,Cristiana Guiducci,James N. Iuliano,Trevor L Kane,Ratul Mukerji,Panga Jaipal Reddy,Janine Powers,M Serrano Rios,Jordan Ye,Carla Barrientos Risso,Daniel Fu-Chang Tsai,Gabriel Pardo,Ryan Q. Notti,Alejandro Pardo,Maurizio Affer,Vindhya Nawaratne,Tulasigeri M. Totiger,Camila Pena-Velasquez,Joanna Rhodes,Andrew D. Zelenetz,Alvaro J. Alencar,Lindsey E. Roeker,Sanjoy Mehta,Ralph Garippa,Adam Linley,David A. Bennett,Sigrid S. Skånland,R. James Brown,Anthony R. Mato,Gwenn M. Hansen,Omar Abdel-Wahab,Justin Taylor
摘要
Increasing use of covalent and noncovalent inhibitors of Bruton’s tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.