过去十年中，针对 BTK 的治疗深刻改变了 CLL 治疗的面貌。猫捉老鼠的抵抗和重新设计的迭代进展已经将 BTK 抑制剂从共价抑制剂转移到非共价抑制剂，现在是靶向蛋白质降解剂。然而，与蛋白质降解剂可能不受 BTK 突变影响的假设相反，我们现在提供的临床证据表明，BTK 激酶结构域（即 A428D）的突变可以赋予目前临床试验中的 BTK 降解剂抗病性，即BGB-16673。 BTK A428D 突变的建模将带负电荷的天冬氨酸取代了临床开发中的另一种 BTK 降解剂（即 NX-2127）的结合口袋内丙氨酸的疏水侧链，这表明具有 BTK A428D 的 CLL 细胞也可能具有耐药性NX-2127，因为已知它们与 BTK 的非共价或共价抑制剂一起使用。因此，临床试验中最先进的两种 BTK 降解剂可能会选择具有 BTK A428D 的 CLL 细胞，这些细胞对所有批准的 BTKi 具有耐药性。© 2024。作者。

Targeting BTK has profoundly changed the face of CLL treatment over the past decade. Iterative advances in the cat and mouse game of resistance and redesign have moved BTK inhibitors from covalent to non-covalent and now targeted protein degraders. However, contrary to the presumption that protein degraders may be impervious to mutations in BTK, we now present clinical evidence that a mutation in the kinase domain of BTK, namely A428D, can confer disease resistance to a BTK degrader currently in clinical trials, that is BGB-16673. Modeling of a BTK A428D mutation places a negatively charged aspartic acid in place of the hydrophobic side chain of alanine within the binding pocket of another BTK-degrader in clinical development, namely NX-2127, suggesting that CLL cells with BTK A428D also may be resistant to NX-2127, as they already are known to be with either non-covalent or covalent inhibitors of BTK. Consequently, the two BTK degraders furthest advanced in clinical trials potentially may select for CLL cells with BTK A428D that are resistant to all approved BTKi's.© 2024. The Author(s).