Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127

• 成果类型: Article
• 署名作者: Montoya, Skye; Bourcier, Jessie; Noviski, Mark; Lu, Hao; Thompson, Meghan C.; Chirino, Alexandra; Jahn, Jacob; Sondhi, Anya K.; Gajewski, Stefan; Tan, Ying Siow (May); Yung, Stephanie; Urban, Aleksandra; Wang, Eric; Han, Cuijuan; Mi, Xiaoli; Kim, Won Jun; Sievers, Quinlan; Auger, Paul; Bousquet, Hugo; Brathaban, Nivetha; Bravo, Brandon; Gessner, Melissa; Guiducci, Cristiana; Iuliano, James N.; Kane, Tim; Mukerji, Ratul; Reddy, Panga Jaipal; Powers, Janine; de los Rios, Mateo Sanchez Garcia; Ye, Jordan; Risso, Carla Barrientos; Tsai, Daniel; Pardo, Gabriel; Notti, Ryan Q.; Pardo, Alejandro; Affer, Maurizio; Nawaratne, Vindhya; Totiger, Tulasigeri M.; Pena-Velasquez, Camila; Rhodes, Joanna M.; Zelenetz, Andrew D.; Alencar, Alvaro; Roeker, Lindsey E.; Mehta, Sanjoy; Garippa, Ralph; Linley, Adam; Soni, Rajesh Kumar; Skanland, Sigrid S.; Brown, Robert J.; Mato, Anthony R.; Hansen, Gwenn M.; Abdel-Wahab, Omar; Taylor, Justin
• 署名单位: University of Miami; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; University of Oslo; University of Oslo; Jackson Laboratory; Rockefeller University; Northwell Health; Memorial Sloan Kettering Cancer Center; University of Liverpool; Columbia University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9219
• DOI: 10.1126/science.adi5798
• 发表日期: 2024-02-02
• 页码: 496-+
• 关键词: brutons tyrosine kinase; therapeutic target; resistance; ibrutinib; ilk; inhibition; activation; mechanisms; maturation; aiolos

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.