Garciaz Sylvain, Saillard Colombe, Hicheri Yosr, Hospital Marie-Anne, Vey Norbert
Aix-Marseille University, INSERM, CNRS, Institut Paoli-Calmettes, 13009 Marseille, France.
Deparment of Hematology, Institut Paoli-Calmettes, 13009 Marseille, France.
Cancers (Basel). 2021 Nov 9;13(22):5608. doi: 10.3390/cancers13225608.
Venetoclax is a BH3-mimetics agent specifically interacting with the antiapoptotic protein BCL-2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Utilization of venetoclax has profoundly changed the landscape of treatment for the poor-prognosis category of AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, Venetoclax, in combination with the hypomethylating agent azacitidine, showed a 65% overall response rate and 14.7-month overall survival, in comparison with 22% and 8 months in the control arm. These results led to the widespread use of venetoclax in this indication. Other combination regimens, consisting of low-intensity, intensive, or targeted therapies are currently under evaluation. Despite promising results, preventing relapses or resistance to venetoclax is still an unmet clinical need. Numerous studies have been conducted to identify and overcome venetoclax resistance in preclinical models or in clinical trials, including the inhibition of other antiapoptotic proteins, the induction of proapoptotic BH3-only proteins, and/or the targeting of the mitochondrial metabolism and machinery.
维奈克拉是一种BH3模拟物，可特异性地与抗凋亡蛋白BCL-2相互作用，促进细胞色素c从线粒体释放，随后激活半胱天冬酶并导致细胞死亡。维奈克拉的应用深刻改变了不适合强化化疗的预后不良急性髓系白血病（AML）患者的治疗格局。在III期VIALE-A研究中，维奈克拉与低甲基化药物阿扎胞苷联合使用时，总缓解率为65%，总生存期为14.7个月，而对照组分别为22%和8个月。这些结果使得维奈克拉在该适应症中得到广泛应用。目前正在评估其他由低强度、强化或靶向治疗组成的联合方案。尽管取得了令人鼓舞的结果，但预防维奈克拉的复发或耐药性仍是尚未满足的临床需求。已经开展了大量研究，以在临床前模型或临床试验中识别并克服维奈克拉耐药性，包括抑制其他抗凋亡蛋白、诱导仅含BH3结构域的促凋亡蛋白，和/或靶向线粒体代谢及机制。
