HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers.
HDAC6 activity is a non-oncogene addiction hub for inflammatory breast cancers.
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DOI：
10.1186/s13058-015-0658-0
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发表时间：
2015-12-08
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影响因子：
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通讯作者：
Silva J
中科院分区：
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作者：
Putcha P;Yu J;Rodriguez-Barrueco R;Saucedo-Cuevas L;Villagrasa P;Murga-Penas E;Quayle SN;Yang M;Castro V;Llobet-Navas D;Birnbaum D;Finetti P;Woodward WA;Bertucci F;Alpaugh ML;Califano A;Silva J
炎症性乳腺癌（IBC）是最致命的乳腺癌形式，5年生存率仅为40%。尽管其致命性，IBC仍然知之甚少，这极大地限制了其治疗管理。因此，我们决定利用整合功能基因组策略来确定IBC细胞的阿喀琉斯之踵。我们率先开发了遗传工具以及实验和分析策略，以在全基因组水平上进行基于RNAi的功能丧失研究。重要的是，我们和其他人已经证明，这些功能筛选能够识别与某些癌症表型相关的基本功能。因此，我们决定使用这种方法来确定IBC特定的敏感性。我们鉴定并验证了HDAC 6作为维持IBC细胞活力的功能必需基因，而对于其他乳腺癌亚型是非必需的。重要的是，HDAC 6的小分子抑制剂已经存在，并正在进行其他肿瘤类型的临床试验。因此，我们证明了Ricolinostat（ACY 1215），一种主要的HDAC 6抑制剂，在体外和体内都有效地控制IBC细胞增殖。重要的是，功能性HDAC 6依赖性与其基因座的基因组改变无关，因此代表非癌基因成瘾。尽管HDAC 6没有过表达，但我们发现其活性在IBC中显著高于非IBC细胞，这表明支持所观察到的依赖性的可能理由。我们发现IBC细胞对HDAC 6抑制敏感，这为快速开发针对IBC患者的新型、有效且耐受性良好的靶向治疗策略提供了基础。本文的在线版本（doi：10.1186/s13058-015-0658-0）包含补充材料，可供授权用户使用。
Inflammatory breast cancer (IBC) is the most lethal form of breast cancers with a 5-year survival rate of only 40 %. Despite its lethality, IBC remains poorly understood which has greatly limited its therapeutic management. We thus decided to utilize an integrative functional genomic strategy to identify the Achilles’ heel of IBC cells. We have pioneered the development of genetic tools as well as experimental and analytical strategies to perform RNAi-based loss-of-function studies at a genome-wide level. Importantly, we and others have demonstrated that these functional screens are able to identify essential functions linked to certain cancer phenotypes. Thus, we decided to use this approach to identify IBC specific sensitivities. We identified and validated HDAC6 as a functionally necessary gene to maintain IBC cell viability, while being non-essential for other breast cancer subtypes. Importantly, small molecule inhibitors for HDAC6 already exist and are in clinical trials for other tumor types. We thus demonstrated that Ricolinostat (ACY1215), a leading HDAC6 inhibitor, efficiently controls IBC cell proliferation both in vitro and in vivo. Critically, functional HDAC6 dependency is not associated with genomic alterations at its locus and thus represents a non-oncogene addiction. Despite HDAC6 not being overexpressed, we found that its activity is significantly higher in IBC compared to non-IBC cells, suggesting a possible rationale supporting the observed dependency. Our finding that IBC cells are sensitive to HDAC6 inhibition provides a foundation to rapidly develop novel, efficient, and well-tolerated targeted therapy strategies for IBC patients. The online version of this article (doi:10.1186/s13058-015-0658-0) contains supplementary material, which is available to authorized users.