Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance.
Targeting BCL-2 in B-cell malignancies and overcoming therapeutic resistance.
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DOI：
10.1038/s41419-020-03144-y
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发表时间：
2020-11-02
影响因子：
9
通讯作者：
Almasan A
中科院分区：
文献类型：
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作者：
Kapoor I;Bodo J;Hill BT;Hsi ED;Almasan A
凋亡缺陷可促进肿瘤发生并损害恶性B细胞对化疗药物的反应。B细胞白血病/淋巴瘤-2（BCL-2）蛋白家族成员是内在线粒体凋亡途径的关键调节因子。抗凋亡BCL-2家族蛋白的过度表达与治疗抵抗和不良预后相关。因此，BCL-2家族蛋白的抑制是依赖于抗凋亡BCL-2家族蛋白的恶性肿瘤的合理治疗选择。维奈托克（ABT-199，GDC-0199）是一种高度选择性的BCL-2抑制剂，代表了该类药物的首个获批药物，目前广泛用于治疗慢性淋巴细胞白血病（CLL）以及急性髓细胞白血病（AML）。尽管有令人印象深刻的临床活性，但长时间的维奈托克单药治疗可能导致耐药性或对靶蛋白的依赖性丧失。在这篇综述中，我们提供了一个概述BCL-2抑制的作用机制和这种方法在目前的B细胞恶性肿瘤的治疗模式中的作用。我们总结了对venetoclax的从头和获得性耐药的驱动因素，这些因素与复杂的克隆转移、BCL-2家族成员、转录调节因子和代谢调节因子的表达和相互作用的相互作用密切相关。我们还研究了最初对venetoclax耐药的肿瘤如何在既往治疗后对其产生反应。在此，我们总结了临床前数据，为维奈托克的有效联合策略提供了理论基础，以通过针对替代抗凋亡BCL-2家族蛋白（MCL-1，BCL-xL），代偿性促生存途径，表观遗传修饰剂和失调的细胞代谢/能量学的靶向方法克服治疗耐药性，以实现持久的临床缓解。
Defects in apoptosis can promote tumorigenesis and impair responses of malignant B cells to chemotherapeutics. Members of the B-cell leukemia/lymphoma-2 (BCL-2) family of proteins are key regulators of the intrinsic, mitochondrial apoptotic pathway. Overexpression of antiapoptotic BCL-2 family proteins is associated with treatment resistance and poor prognosis. Thus, inhibition of BCL-2 family proteins is a rational therapeutic option for malignancies that are dependent on antiapoptotic BCL-2 family proteins. Venetoclax (ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor that represents the first approved agent of this class and is currently widely used in the treatment of chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML). Despite impressive clinical activity, venetoclax monotherapy for a prolonged duration can lead to drug resistance or loss of dependence on the targeted protein. In this review, we provide an overview of the mechanism of action of BCL-2 inhibition and the role of this approach in the current treatment paradigm of B-cell malignancies. We summarize the drivers of de novo and acquired resistance to venetoclax that are closely associated with complex clonal shifts, interplay of expression and interactions of BCL-2 family members, transcriptional regulators, and metabolic modulators. We also examine how tumors initially resistant to venetoclax become responsive to it following prior therapies. Here, we summarize preclinical data providing a rationale for efficacious combination strategies of venetoclax to overcome therapeutic resistance by a targeted approach directed against alternative antiapoptotic BCL-2 family proteins (MCL-1, BCL-xL), compensatory prosurvival pathways, epigenetic modifiers, and dysregulated cellular metabolism/energetics for durable clinical remissions.
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影响因子：
--
作者：
Bodo J;Zhao X;Durkin L;Souers AJ;Phillips DC;Smith MR;Hsi ED
通讯作者：
Hsi ED
影响因子：
12.4
作者：
Adams JM;Cory S
通讯作者：
Cory S
影响因子：
50.3
作者：
Certo, Michael;Moore, Victoria Del Gaizo;Letai, Anthony
通讯作者：
Letai, Anthony
影响因子：
37.3
作者：
Al-Harbi S;Choudhary GS;Ebron JS;Hill BT;Vivekanathan N;Ting AH;Radivoyevitch T;Smith MR;Shukla GC;Almasan A
通讯作者：
Almasan A
影响因子：
28.2
作者：
Caenepeel, Sean;Brown, Sean P.;Hughes, Paul E.
通讯作者：
Hughes, Paul E.