Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics.
Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics.
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DOI：
10.1126/scisignal.abc7405
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发表时间：
2021-06-08
影响因子：
7.3
通讯作者：
Letai A
中科院分区：
文献类型：
--
作者：
Daniels VW;Zoeller JJ;van Gastel N;McQueeney KE;Parvin S;Potter DS;Fell GG;Ferreira VG;Yilma B;Gupta R;Spetz J;Bhola PD;Endress JE;Harris IS;Carrilho E;Sarosiek KA;Scadden DT;Brugge JS;Letai A
与非恶性细胞相比，癌细胞具有不同的代谢依赖性。然而，很少有代谢靶向化合物在临床试验中取得成功。在这里，我们研究了三阴性乳腺癌（TNBC）的代谢脆弱性，特别是那些代谢扰动增加线粒体凋亡启动和对BH3模拟物（拮抗凋亡蛋白的药物）的敏感性。我们使用高通量动态BH3谱分析（HT-DBP）筛选代谢干扰小分子库，发现烟酰胺磷酸核糖基转移酶（NAMPT）抑制剂是首选候选。在一些TNBC细胞中，而非恶性细胞中，NAMPT抑制剂增加了总体凋亡启动，并诱导对特定抗凋亡BCL-2家族成员的依赖。用NAMPT抑制剂治疗TNBC细胞使它们对随后的BH3模拟物治疗敏感。NAMPT抑制剂（FK866）和MCL-1拮抗剂（S63845）的联合使用在体内可降低TNBC患者来源的异种移植模型中的肿瘤生长。我们发现NAMPT抑制将NAD+浓度降低到一个临界阈值以下，从而导致腺嘌呤的消耗，腺嘌呤是引发TNBC细胞凋亡的代谢触发器。这些发现证明了代谢和线粒体凋亡信号通路之间的密切相互作用，并揭示了利用肿瘤特异性代谢易感性可以使一些TNBC对BH3模拟物敏感。
Cancer cells have differential metabolic dependencies compared to their non-malignant counterparts. However, few metabolism-targeting compounds have been successful in clinical trials. Here, we investigated the metabolic vulnerabilities of triple-negative breast cancer (TNBC), in particular those metabolic perturbations that increased mitochondrial apoptotic priming and sensitivity to BH3 mimetics (drugs that antagonize anti-apoptotic proteins). We used high throughput-dynamic BH3 profiling (HT-DBP) to screen a library of metabolism-perturbing small molecules, which revealed inhibitors of the enzyme nicotinamide phosphoribosyltransferase (NAMPT) as top candidates. In some TNBC cells but not in non-malignant cells, NAMPT inhibitors increased overall apoptotic priming and induced dependencies on specific anti-apoptotic BCL-2 family members. Treatment of TNBC cells with NAMPT inhibitors sensitized them to subsequent treatment with BH3 mimetics. The combination of a NAMPT inhibitor (FK866) and an MCL-1 antagonist (S63845) reduced tumor growth in a TNBC patient-derived xenograft model in vivo. We found that NAMPT inhibition reduced NAD+ concentrations below a critical threshold that resulted in depletion of adenine, which was the metabolic trigger that primed TNBC cells for apoptosis. These findings demonstrate a close interaction between metabolic and mitochondrial apoptotic signaling pathways and reveal that exploitation of a tumor-specific metabolic vulnerability can sensitize some TNBC to BH3 mimetics.
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影响因子：
20.3
作者：
Anderson, Mary Ann;Deng, Jing;Roberts, Andrew W.
通讯作者：
Roberts, Andrew W.
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
16
作者：
Bhola PD;Letai A
通讯作者：
Letai A
影响因子：
50.3
作者：
Certo, Michael;Moore, Victoria Del Gaizo;Letai, Anthony
通讯作者：
Letai, Anthony
影响因子：
64.8
作者：
Chowdhry, Sudhir;Zanca, Ciro;Mischel, Paul S.
通讯作者：
Mischel, Paul S.