Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy
Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy
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DOI：
10.1126/scitranslmed.aaa4642
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发表时间：
2015-03-18
影响因子：
17.1
通讯作者：
Souers, Andrew J.
中科院分区：
文献类型：
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作者：
Leverson, Joel D.;Phillips, Darren C.;Souers, Andrew J.
BCL-2/BCL-X-L/BCL-W抑制剂ABT-263 （navitoclax）在慢性淋巴细胞白血病等淋巴细胞恶性肿瘤中显示出良好的临床活性。然而，由于BCL-X-L抑制引起的血小板减少症，其在这些情况下的疗效受到限制。这促使bcl -2选择性抑制剂venetoclax （ABT-199/GDC0199）的产生，该抑制剂在这些癌症中显示出强大的活性，但会保留血小板。Navitoclax也被证明可以增强多西他赛在实体瘤临床前模型中的疗效，但这种组合的临床使用受到中性粒细胞减少症的限制。我们使用venetoclax和BCL-X-L选择性抑制剂A-1155463和A-1331852来评估抑制BCL-2或BCL-X-L对navitoclax-docetaxel联合治疗的疗效和毒性的相对贡献。选择性BCL-2抑制抑制了体外和体内的粒细胞生成，这可能是临床上navitoclax与多西他赛联合使用时中性粒细胞减少加剧的原因。相比之下，选择性抑制BCL-X-L不抑制颗粒生成，但在对一系列实体瘤的测试中，与多西紫杉醇联合使用时非常有效。因此，bcl - x - l选择性抑制剂有可能增强多西紫杉醇在实体肿瘤中的疗效，避免纳维托克拉西观察到的中性粒细胞减少症加重。这些研究证明了选择性BCL-2家族抑制剂工具包的转化效用，并强调了它们作为改进癌症治疗方法的潜力。
The BCL-2/BCL-X-L/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-X-L inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-X-L-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-X-L to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-X-L did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-X-L-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.