肿瘤预防与治疗2026，Vol.39Issue(1)：58-64,7.DOI:10.3969/j.issn.1674-0904.2026.01.009
B细胞淋巴瘤中BTKi耐药的研究现状与展望
Evolving Landscape of Resistance to Bruton's Tyrosine Kinase Inhibitors in B-Cell Lymphomas
摘要
Abstract
Bruton's tyrosine kinase inhibitors(BTKi),such as ibrutinib,acalabrutinib,and zanubrutinib,have become important targeted drugs for treating B-cell malignancies like chronic lymphocytic leukemia and have significantly improved patient outcomes.However,acquired resistance resulting from long-term use poses a major clinical challenge.A primary mechanism of BTKi resistance involves mutations in the BTK gene,notably the C481S mutation.This mutation disrupts the binding of covalent BTKi,thereby leading to drug resistance.Additionally,mutations in PLCG2 gene and non-C481 sites(notably T474I and L528W)have been shown to mediate resistance to both covalent and non-covalent BTKi.Novel non-cova-lent BTKi such as pirtobrutinib can overcome this resistance by reversibly binding to BTK independently of the C481 site,thereby restoring inhibition of some resistant cells.In contrast,BTK degraders that utilize PROTAC technology directly de-grade the BTK protein itself.This mechanism has demonstrated activity against a broad range of resistance mutations in pre-clinical studies,presenting a promising strategy to overcome drug resistance.In summary,exploring the mechanisms of BTKi resistance and developing next-generation therapies—in-cluding non-covalent inhibitors and protein degraders—are es-sential to improve outcomes and extend survival for patients.关键词
B细胞淋巴瘤/布鲁顿酪氨酸激酶抑制剂(BTKi)/耐药/B细胞恶性肿瘤/获得性耐药Key words
B-cell lymphoma/Bruton's tyrosine kinase inhibitor(BTKi)/Resistance/B-cell malignancies/Acquired resistance分类
医药卫生引用本文复制引用
刘芷兮,张音洁,李仁琴,谢燕达,王鉴,邱悦..B细胞淋巴瘤中BTKi耐药的研究现状与展望[J].肿瘤预防与治疗,2026,39(1):58-64,7.基金项目
This study was supported by grants from Sichuan Cancer Hospital(No.YB2024006). 四川省肿瘤医院优秀青年基金(编号:YB2024006) （No.YB2024006）
