Bravo-Gonzalez Andres, Alasfour Maryam, Soong Deborah, Noy Jose, Pongas Georgios
London School of Hygiene and Tropical Medicine, Bogotá 110221, Colombia.
Department of Medicine, University of Miami and Jackson Memorial Hospital, Miami, FL 33136, USA.
Cancers (Basel). 2024 Oct 10;16(20):3434. doi: 10.3390/cancers16203434.
B-cell lymphoid malignancies are a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, Ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors (BTKi) can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTKi, such as Pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTKi. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTKi and the development of new therapeutic strategies highlight the ongoing advances being made towards the pursuit of a cure for B-cell lymphoid malignancies.
B细胞淋巴恶性肿瘤是一组异质性血液系统癌症，其中布鲁顿酪氨酸激酶（BTK）抑制剂已获得FDA批准用于多种亚型。一流的共价BTK抑制剂伊布替尼与C481氨基酸残基结合，以阻断BTK酶并防止下游信号传导。对共价BTK抑制剂（BTKi）的耐药性可通过BTK结合位点（C481S）的突变产生，但也可通过其他BTK位点和磷脂酶Cγ2（PLCγ2）的突变导致下游信号传导。为了绕过C481S突变，开发了非共价BTKi，如派罗替尼，它对野生型和C481S突变均有活性。在本综述中，我们讨论了导致对共价和非共价BTKi产生耐药性的分子和遗传机制。此外，我们还讨论了新兴的BTK降解剂类别，它们利用靶向蛋白水解嵌合体（PROTAC）的进化来降解BTK蛋白，构成了克服耐药性的重要途径。BTKi耐药性的动态变化以及新治疗策略的发展突出了在寻求治愈B细胞淋巴恶性肿瘤方面正在取得的持续进展。
