Clinical Hematology, Nantes University Hospital, 1 place A. Ricordeau, 44000 Nantes, France.
CRCINA, INSERM, CNRS, Angers University, Nantes University, 8 quai Moncousu, 44000 Nantes, France.
Cells. 2020 Mar 14;9(3):717. doi: 10.3390/cells9030717.
Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-X) is a common hallmark in cancers. To divert this dysregulation into vulnerability, researchers have developed BH3 mimetics, which are small molecules that restore effective apoptosis in neoplastic cells by interfering with anti-apoptotic proteins. Among them, venetoclax is a potent and selective BCL-2 inhibitor, which has demonstrated the strongest clinical activity in mature B-cell malignancies, including chronic lymphoid leukemia, mantle-cell lymphoma, and multiple myeloma. Nevertheless, mechanisms of primary and acquired resistance have been recently described and several features such as cytogenetic abnormalities, BCL-2 family expression, and ex vivo drug testing have to be considered for predicting sensitivity to BH3 mimetics and helping in the identification of patients able to respond. The medical need to overcome resistance to BH3 mimetics supports the evaluation of innovative combination strategies. Novel agents including MCL-1 targeting BH3 mimetics are currently evaluated and may represent new therapeutic options in the field. The present review summarizes the current knowledge regarding venetoclax and other BH3 mimetics for the treatment of mature B-cell malignancies.
细胞凋亡是一种高度保守的机制，可促使清除不需要的细胞。线粒体凋亡受 B 细胞淋巴瘤（BCL-2）家族调控，包括抗凋亡和促凋亡蛋白。通过抗凋亡 BCL-2 家族成员（BCL-2、MCL-1、BCL-X）的失调而逃避凋亡是癌症的常见特征。为了将这种失调转化为易感性，研究人员开发了 BH3 模拟物，这是一种小分子，通过干扰抗凋亡蛋白来恢复肿瘤细胞中有效的细胞凋亡。其中，venetoclax 是一种强效且选择性的 BCL-2 抑制剂，在成熟 B 细胞恶性肿瘤中表现出最强的临床活性，包括慢性淋巴细胞白血病、套细胞淋巴瘤和多发性骨髓瘤。然而，最近已经描述了原发性和获得性耐药的机制，并且必须考虑细胞遗传学异常、BCL-2 家族表达和体外药物测试等几个特征，以预测对 BH3 模拟物的敏感性，并帮助识别能够应答的患者。克服对 BH3 模拟物的耐药性的医疗需求支持评估创新的联合策略。目前正在评估包括靶向 MCL-1 的 BH3 模拟物在内的新型药物，它们可能是该领域的新治疗选择。本综述总结了 venetoclax 和其他用于治疗成熟 B 细胞恶性肿瘤的 BH3 模拟物的最新知识。
