Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma.
Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma.
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DOI：
10.1038/s41467-023-38552-z
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发表时间：
2023-05-20
影响因子：
16.6
通讯作者：
Letai, Anthony
中科院分区：
文献类型：
--
作者：
Potter, Danielle S. S.;Du, Ruochen;Bohl, Stephan R. R.;Chow, Kin-Hoe;Ligon, Keith L. L.;Bueno, Raphael;Letai, Anthony
恶性胸膜间皮瘤（MPM）对晚期疾病的一线/二线治疗相对无效，早期疾病的5年生存率仅为18%。通过动态BH3谱测量的药物诱导线粒体启动识别多种疾病环境中的有效药物。我们使用高通量动态BH3分析（HTDBP）来鉴定药物组合，这些药物组合可以启动来自患者肿瘤的原代MPM细胞，也可以启动患者来源的异种移植（PDX）模型。navitoclax （BCL-xL/BCL-2/BCL-w拮抗剂）和AZD8055 （mTORC1/2抑制剂）联合在MPM PDX模型中显示出体内疗效，验证了HTDBP作为鉴定有效药物组合的方法。机制研究表明，AZD8055治疗降低了MCL-1蛋白水平，增加了BIM蛋白水平，增加了MPM线粒体对BCL-xL的依赖，navitoclax利用了BCL-xL。Navitoclax治疗增加了对MCL-1的依赖性，并增加了BIM蛋白水平。这些发现表明，HTDBP可作为功能性精准医疗工具，合理构建MPM及其他肿瘤的联合用药方案。恶性胸膜间皮瘤（MPM）是一种侵袭性恶性肿瘤，几乎没有有效的治疗选择。在这里，作者使用动态BH3谱分析来测量药物诱导的线粒体启动，并在离体和临床前MPM模型中鉴定AZD8055和navitoclax作为促凋亡药物组合。
Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers. Malignant pleural mesothelioma (MPM) is an aggressive malignancy with few effective treatment options available. Here, the authors use dynamic BH3 profiling to measure drug-induced mitochondrial priming and identify AZD8055 and navitoclax as a pro-apoptotic drug combination in ex vivo and preclinical MPM models.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
3.7
作者：
Guzmán C;Bagga M;Kaur A;Westermarck J;Abankwa D
通讯作者：
Abankwa D
影响因子：
7
作者：
Arulananda S;O'Brien M;Evangelista M;Jenkins LJ;Poh AR;Walkiewicz M;Leong T;Mariadason JM;Cebon J;Balachander SB;Cidado JR;Lee EF;John T;Fairlie WD
通讯作者：
Fairlie WD
DOI：
10.1073/pnas.1411848112
发表时间：
2015-03-17
影响因子：
11.1
作者：
Faber, Anthony C.;Farago, Anna F.;Engelman, Jeffrey A.
通讯作者：
Engelman, Jeffrey A.
影响因子：
11.2
作者：
Daniel VC;Marchionni L;Hierman JS;Rhodes JT;Devereux WL;Rudin CM;Yung R;Parmigiani G;Dorsch M;Peacock CD;Watkins DN
通讯作者：
Watkins DN