Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Science. 2024 Feb 2;383(6682):eadi5798. doi: 10.1126/science.adi5798.
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.
越来越多的布鲁顿酪氨酸激酶（BTK）共价和非共价抑制剂的使用阐明了一系列在 B 细胞恶性肿瘤患者中获得性耐药 BTK 突变。在这里，我们确定了具有不同酶活性的 BTK 抑制剂耐药突变，包括一些可削弱 BTK 酶活性，同时赋予维持 B 细胞受体（BCR）信号的新型蛋白-蛋白相互作用的突变。此外，我们描述了一种临床阶段的 BTK 和 IKZF1/3 降解剂 NX-2127，它可以结合和蛋白酶体降解每种突变的 BTK 蛋白水解产物，从而有效地阻断 BCR 信号。用 NX-2127 治疗慢性淋巴细胞白血病可使患者体内 BTK 降解超过 80%，并证明了治疗的概念验证。这些数据揭示了突变 BTK 的致癌支架功能，它可在临床上批准的 BTK 抑制剂中产生耐药性，但在患者中可通过 BTK 降解来克服。
