Pathways and mechanisms of venetoclax resistance.
Pathways and mechanisms of venetoclax resistance.
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DOI：
10.1080/10428194.2017.1283032
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发表时间：
2017-09
影响因子：
2.6
通讯作者：
Konopleva M
中科院分区：
文献类型：
--
作者：
Bose P;Gandhi V;Konopleva M
维奈托克是BCL-2抗凋亡蛋白的“BH 3模拟物”拮抗剂，其获批用于慢性淋巴细胞白血病是转译凋亡研究的一个重要里程碑。维奈托克已经获得了急性髓性白血病的“突破性”称号，并正在研究许多其他类型的肿瘤。然而，对BCL-2抑制剂单药治疗的耐药性可能很快发生。几项研究表明，其他两种主要的抗凋亡BCL-2家族蛋白BCL-XL和MCL-1是对维奈托克耐药的主要决定因素。这为合理地将venetoclax与其他靶向药物结合以避免耐药性开辟了可能性。在这里，我们总结了最有前途的组合，并强调那些已经在临床试验。人们也越来越认识到，不同的肿瘤显示不同程度的成瘾个别BCL-2家族蛋白，并需要完善目前的“BH 3谱”技术。最后，人们迫切期待着BCL-XL和MCL-1的有效和选择性拮抗剂的成功临床开发。
The approval of venetoclax, a “BH3-mimetic” antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received “breakthrough” designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are the main determinants of resistance to venetoclax. This opens up possibilities for rationally combining venetoclax with other targeted agents to circumvent resistance. Here, we summarize the most promising combinations, and highlight those already in clinical trials. There is also increasing recognition that different tumors display different degrees of addiction to individual BCL-2 family proteins, and of the need to refine current “BH3 profiling” techniques. Finally, the successful clinical development of potent and selective antagonists of BCL-XL and MCL-1 is eagerly awaited.