Drug Repurposing Applications to Overcome Male Predominance via Targeting G2/M Checkpoint in Human Esophageal Squamous Cell Carcinoma.
Drug Repurposing Applications to Overcome Male Predominance via Targeting G2/M Checkpoint in Human Esophageal Squamous Cell Carcinoma.
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通过针对人食管鳞状细胞癌 G2/M 检查点的药物再利用来克服男性优势
DOI：
10.3390/cancers14235854
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发表时间：
2022-11-28
期刊：
影响因子：
5.2
通讯作者：
Liu, Zhihua
中科院分区：
文献类型：
--
作者：
Yin, Yin;Yu, Xiao;Feng, Riyue;Li, Yang;Zhao, Yahui;Liu, Zhihua
在大多数癌症类型中，癌症发病率和癌症死亡率存在性别偏见。食道鳞状细胞癌(ESCC)是一种典型的恶性肿瘤，男性死亡率较高，治疗反应较差。为了克服男性在ESCC中的优势，需要确定更多的治疗靶点。同时，年龄也是一个重要的因素，当我们考虑癌症的性别偏见时，应该包括在内。在这项研究中，我们使用了来自663名ESCC患者的多组学数据，发现G2/M检查点通路相关的性别偏见和年龄偏见显著地存在于基因组学、转录组和表观基因组学中。我们的研究结果表明，G2/M靶点可能被包括在男性患者的联合治疗中，以提高ESCC的疗效。食道鳞状细胞癌(ESCC)以男性为主，死亡率较高，对治疗反应较差。尽管性激素发挥了作用，但其他可能导致ESCC性别偏见的原因在很大程度上仍不清楚，特别是随着年龄的增长和性别之间的荷尔蒙差异开始缩小。在这项研究中，我们分析了663例ESCC患者的基因组学、转录组学和表观基因组学，发现G2/M检查点通路相关的性别偏见和年龄偏见显著地存在于多组学数据中。根据不同性别的基因表达模式，通过应用药物再利用从三个药物敏感性数据库：连接图谱(Cmap)、癌症药物敏感性基因组学(GDSC)和癌症治疗反应门户网站(CTRP)中鉴定出10个化合物。MK1775和地西他滨在体外和体内对两种雄性ESCC细胞株均有较好的疗效。这些药物与G2和M之间的转变有关，在雄性细胞系中尤其明显。在我们的研究中，我们首先验证了G2/M检查点通路在ESCC中的性别偏见，然后确定G2/M靶点可能被包括在男性患者的联合治疗中，以提高ESCC的治疗效果。
Sex biases in cancer incidence and cancer mortality exist in the majority of cancer types. Esophageal squamous cell carcinoma (ESCC) is a typical malignancy with higher mortality rates and worse responses to treatment in males versus females. To overcome the male predominance in ESCC, more therapeutic targets need to be identified. Meanwhile, age is also an important contributor that should be included when we consider sex bias in cancer. In this study, we used multi-omics data from 663 ESCC patients and found that G2/M checkpoint pathway-related sex bias and age bias were significantly present in genomics, transcriptomics, and epigenomics. Our findings suggest that G2/M targets may be included in combination therapy for male patients to improve the efficacy of ESCC treatment. Esophageal squamous cell carcinoma (ESCC) is strongly characterized by a male predominance with higher mortality rates and worse responses to treatment in males versus females. Despite the role of sex hormones, other causes that may contribute to sex bias in ESCC remain largely unknown, especially as age increases and the hormone difference begins to diminish between sexes. In this study, we analyzed genomics, transcriptomics, and epigenomics from 663 ESCC patients and found that G2/M checkpoint pathway-related sex bias and age bias were significantly present in multi-omics data. In accordance with gene expression patterns across sexes, ten compounds were identified by applying drug repurposing from three drug sensitivity databases: The Connective Map (CMap), Genomics of Drug Sensitivity in Cancer (GDSC), and The Cancer Therapeutic Response Portal (CTRP). MK1775 and decitabine showed better efficacy in two male ESCC cell lines in vitro and in vivo. The drugs’ relevance to the transition between G2 and M was especially evident in male cell lines. In our study, we first validated the sex bias of the G2/M checkpoint pathway in ESCC and then determined that G2/M targets may be included in combination therapy for male patients to improve the efficacy of ESCC treatment.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
64.5
作者：
Basu A;Bodycombe NE;Cheah JH;Price EV;Liu K;Schaefer GI;Ebright RY;Stewart ML;Ito D;Wang S;Bracha AL;Liefeld T;Wawer M;Gilbert JC;Wilson AJ;Stransky N;Kryukov GV;Dancik V;Barretina J;Garraway LA;Hon CS;Munoz B;Bittker JA;Stockwell BR;Khabele D;Stern AM;Clemons PA;Shamji AF;Schreiber SL
通讯作者：
Schreiber SL
癌症死亡率和生存中的性别差异。
DOI：
10.1158/1055-9965.epi-11-0246
发表时间：
2011-08
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
--
作者：
Cook MB;McGlynn KA;Devesa SS;Freedman ND;Anderson WF
通讯作者：
Anderson WF
DOI：
10.1038/s41568-021-00348-y
发表时间：
2021-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Haupt S;Caramia F;Klein SL;Rubin JB;Haupt Y
通讯作者：
Haupt Y
影响因子：
12.3
作者：
Akalin A;Kormaksson M;Li S;Garrett-Bakelman FE;Figueroa ME;Melnick A;Mason CE
通讯作者：
Mason CE