维奈克拉治疗急性髓系白血病的耐药机制及应对策略

Mechanism of drug resistance and strategy for Venetoclax in acute myeloid leukemia

急性髓系白血病(AML)是一类克隆性造血干细胞恶性肿瘤,治疗手段有限,死亡率高,但是近些年涌现多种靶向药物有望改善这一困境。2018年经FDA批准的维奈克拉(Venetoclax)极大地提高了AML患者的应答率。Venetoclax是一种BH3模拟物,它特异性地抑制抗凋亡蛋白BCL-2,进而杀伤肿瘤细胞。然而,随着Venetoclax在AML中的广泛应用,其耐药问题逐渐显现。具体的耐药机制主要表现在肿瘤细胞中靶点蛋白BCL-2下调及其他非BCL-2抗凋亡蛋白上调、BCL-2家族中促凋亡蛋白下调及非依赖BCL-2家族蛋白的其他耐药机制。本综述将系统地阐述AML中Venetoclax耐药的分子机制,并总结靶向这些耐药机制的相关治疗策略的新进展。

Acute myeloid leukemia(AML)is a hematologic malignancy characterized by a low remission and short survival.Fortunately,various targeted drugs in recent year may improve this challenging scenario.Among them,Venetoclax,approved by the FDA in 2018,has significantly enhanced the responses in AML patients.As a BH3 mimic,Venclexta induces tumor cell death by selectively binding to BCL-2 and inhibiting its anti-apoptotic function.However,with the wide use of Venetoclax in various AML scenarios,drug resistance has gradually become an issue.The specific mechanism of drug resistance in tumor cells includes:downregulation of BCL-2 and upregulation of other anti-apoptotic proteins,downregulation of pro-apoptotic proteins within the BCL-2 family,and other mechanisms independent of BCL-2 family proteins.This review systematically explained the molecular mechanism underlying Venetoclax resistance in AML and summarized strategies for addressing these problems.