Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127
Skye Montoya, Jessie Bourcier, Mark Noviski, Hao Lu, Meghan C. Thompson, Alexandra Chirino, Jacob Jahn, Anya K. Sondhi, Stefan Gajewski, Y. Tan, Stephanie Yung, Aleksandra Urban, Eric Wang, Cuijuan Han, Xiaoli Mi, Won Jun Kim, Quinlan Sievers, P Auger, Hugo Bousquet, Nivetha Brathaban, Brandon Bravo, Melissa Gessner, Cristiana Guiducci, James N. Iuliano, Tim Kane, Ratul Mukerji, Panga Jaipal Reddy, Janine Powers, Mateo Sanchez Garcia de los Rios, Jordan Ye, Carla Barrientos Risso, Daniel 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 J. Linley, Rajesh K. Soni, Sigrid S. Skånland, Robert J. Brown, Anthony R. Mato, Gwenn M. Hansen, Omar Abdel‐Wahab, Justin Taylor
Abstract
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.