Article
作者: Skånland, Sigrid S ; Hansen, Gwenn M ; Mi, Xiaoli ; Brathaban, Nivetha ; Noviski, Mark ; Roeker, Lindsey E ; Ye, Jordan ; Bousquet, Hugo ; Barrientos Risso, Carla ; Kim, Won Jun ; Rhodes, Joanna M ; Thompson, Meghan C ; Sievers, Quinlan ; Guiducci, Cristiana ; Sondhi, Anya K ; Reddy, Panga Jaipal ; Soni, Rajesh Kumar ; Nawaratne, Vindhya ; Yung, Stephanie ; Han, Cuijuan ; Abdel-Wahab, Omar ; Pardo, Alejandro ; Gessner, Melissa ; Linley, Adam ; Powers, Janine ; Tsai, Daniel ; Affer, Maurizio ; Montoya, Skye ; Brown, Robert J ; Pena-Velasquez, Camila ; Sanchez Garcia de Los Rios, Mateo ; Taylor, Justin ; Tan, Ying Siow May ; Lu, Hao ; Zelenetz, Andrew D ; Totiger, Tulasigeri M ; Chirino, Alexandra ; Gajewski, Stefan ; Mato, Anthony R ; Kane, Tim ; Bourcier, Jessie ; Mehta, Sanjoy ; Wang, Eric ; Jahn, Jacob ; Notti, Ryan Q ; Bravo, Brandon ; Garippa, Ralph ; Alencar, Alvaro ; Iuliano, James N ; Pardo, Gabriel ; Auger, Paul ; Mukerji, Ratul ; Urban, Aleksandra
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.