B细胞淋巴瘤中BTKi耐药的研究现状与展望OA

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.