Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737
Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737
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DOI：
10.1073/pnas.1104778108
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发表时间：
2012-02-21
影响因子：
11.1
通讯作者：
Lindeman, Geoffrey J.
中科院分区：
文献类型：
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作者：
Oakes, Samantha R.;Vaillant, Francois;Lindeman, Geoffrey J.
生存蛋白bcl2的过度表达在乳腺癌中很常见。在这里，我们探索了它作为这种疾病潜在治疗靶点的作用。BCL-2及其抗凋亡相关基因MCL-1和BCL-XL，以及促凋亡的BH3配体BIM被发现在相当大比例的异质性乳腺肿瘤中共表达，包括临床上侵袭性的基底细胞样癌。为了确定中和bcl2、bclxl和bclW的BH3模拟ABT-737在靶向bcl2表达的基底样三阴性肿瘤方面是否具有潜在的疗效，我们在免疫低下的小鼠和接受ABT-737、多西紫杉醇或其组合治疗的受者中产生了一组原发乳腺肿瘤异种移植瘤。联合治疗可显著改善肿瘤反应和总体存活率，但仅限于bcl2表达水平升高的肿瘤移植瘤。ABT-737单独治疗无效，表明ABT-737使肿瘤细胞对多西紫杉醇敏感。联合治疗伴有明显的细胞凋亡增加和BIM与bcl-2的解离。值得注意的是，BH3模拟似乎在表达bcl2的异种移植株中也有效，这些异种移植株含有p53突变。我们的发现提供了体内证据，表明BH3类似物可用于提高乳腺癌对化疗的敏感性，并进一步表明bcl2表达升高是乳腺癌的预测性反应标记物。
Overexpression of the prosurvival protein BCL-2 is common in breast cancer. Here we have explored its role as a potential therapeutic target in this disease. BCL-2, its anti-apoptotic relatives MCL-1 and BCL-XL, and the proapoptotic BH3-only ligand BIM were found to be coexpressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers. To determine whether the BH3 mimetic ABT-737 that neutralizes BCL-2, BCL-XL, and BCL-W had potential efficacy in targeting BCL-2-expressing basal-like triple-negative tumors, we generated a panel of primary breast tumor xenografts in immunocompromised mice and treated recipients with either ABT-737, docetaxel, or a combination. Tumor response and overall survival were significantly improved by combination therapy, but only for tumor xenografts that expressed elevated levels of BCL-2. Treatment with ABT-737 alone was ineffective, suggesting that ABT-737 sensitizes the tumor cells to docetaxel. Combination therapy was accompanied by a marked increase in apoptosis and dissociation of BIM from BCL-2. Notably, BH3 mimetics also appeared effective in BCL-2-expressing xenograft lines that harbored p53 mutations. Our findings provide in vivo evidence that BH3 mimetics can be used to sensitize primary breast tumors to chemotherapy and further suggest that elevated BCL-2 expression constitutes a predictive response marker in breast cancer.