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）抑制剂已获得美国食品药品监督管理局批准用于多种亚型治疗。首创共价BTK抑制剂伊布替尼通过结合C481氨基酸残基阻断BTK酶活性，从而抑制下游信号传导。共价BTK抑制剂耐药机制除BTK结合位点突变（C481S）外，还可涉及其他BTK位点及磷脂酶Cγ2（PLCγ2）突变导致下游信号持续激活。为规避C481S突变，非共价BTK抑制剂（如吡托布鲁替尼）应运而生，该类药物对野生型及C481S突变型均具有活性。本综述系统阐述了共价与非共价BTK抑制剂获得性耐药的分子遗传学机制，并探讨了新兴的BTK降解剂——该类疗法利用蛋白水解靶向嵌合体技术降解BTK蛋白，为克服耐药开辟了重要途径。BTK抑制剂耐药格局的动态演变及新型治疗策略的不断发展，彰显了B细胞淋巴恶性肿瘤治疗领域持续迈向治愈目标的重大进展。
肿瘤(癌症)患者之家