BCL-2抑制剂在血液恶性肿瘤中的靶向治疗应用及作用机制

The targeted therapy and mechanism of BCL-2 inhibitor in hematological malignancies

细胞凋亡受到抑制是血液恶性肿瘤细胞的突出特征。B细胞淋巴瘤-2(B-cell lymphoma-2,BCL-2)是细胞凋亡关键性蛋白调节因子,在多种血液恶性肿瘤中有不同程度的表达。高表达BCL-2的肿瘤细胞抗细胞凋亡能力显著增强,靶向抑制BCL-2成为抗血液肿瘤的研究热点之一。维奈克拉是首个获批上市的BCL-2抑制剂(BCL-2 inhibitor,BCL-2i),用于慢性淋巴细胞白血病、急性髓系白血病及骨髓增生异常综合征的治疗。研究表明维奈克拉对其他血液恶性肿瘤如B细胞非霍奇金淋巴瘤及多发性骨髓瘤也具有抗肿瘤活性。本文就BCL-2抗凋亡机制、BCL-2i在血液恶性肿瘤中的临床应用以及BCL-2i耐药的可能机制作一简要综述。

Inhibition of apoptosis is a prominent feature of hematological malignancies.B-cell lymphoma-2(BCL-2)is a key protein regulator of apoptosis and is expressed to varying degrees in a variety of hematological malignancies.The anti-apoptotic ability of tumor cells with high expression of BCL-2 is significantly enhanced,and targeted inhibition of BCL-2 has become one of the research hotspots in anti-hematological tumors.Venetoclax(VEN)is the first BCL-2 inhibitor(BCL-2i)approved for the treatment of chronic lymphocytic leukemia,acute myeloid leukemia and myelodysplastic syndromes.Studies have shown that VEN also has antitumor activity against other hematological malignancies such as B-cell non-Hodgkin lymphomas and multiple myeloma.This article briefly reviews the anti-apoptosis mechanism of BCL-2,the clinical application of BCL-2i in hematological malignancies,and the possible mechanism of BCL-2i resistance.