Synthetic lethal screen of an EGFR-centered network to improve targeted therapies.
Synthetic lethal screen of an EGFR-centered network to improve targeted therapies.
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DOI：
10.1126/scisignal.2001083
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发表时间：
2010-09-21
影响因子：
7.3
通讯作者：
Golemis EA
中科院分区：
文献类型：
--
作者：
Astsaturov I;Ratushny V;Sukhanova A;Einarson MB;Bagnyukova T;Zhou Y;Devarajan K;Silverman JS;Tikhmyanova N;Skobeleva N;Pecherskaya A;Nasto RE;Sharma C;Jablonski SA;Serebriiskii IG;Weiner LM;Golemis EA
内在和获得性细胞抗性因子限制了大多数靶向癌症治疗剂的功效。低等真核生物的合成致死筛选表明，与治疗靶点密切相关的基因网络将富集耐药性的决定因素。我们开发了一个以表皮生长因子受体（EGFR）为中心的蛋白质网络，EGFR是一种经过验证的癌症治疗靶点，并使用siRNA筛选来比较探测该网络中调节EGFR靶向药物和非特异性细胞毒性药物有效性的蛋白质。我们确定了影响抗性的蛋白质的子网络，推定的抗性决定因素在与网络核心蛋白质相互作用的蛋白质中富集。我们发现EGFR拮抗剂和临床相关药物靶向EGFR网络中连接的蛋白质，如激酶蛋白激酶C或Aurora激酶A，或转录调节因子STAT3，协同降低细胞活力和肿瘤大小，这表明有可能直接用于临床开发。这种集中的方法可以潜在地改善联合癌症疗法的连贯设计。
Intrinsic and acquired cellular resistance factors limit the efficacy of most targeted cancer therapeutics. Synthetic lethal screens in lower eukaryotes suggest that networks of genes closely linked to therapeutic targets would be enriched for determinants of drug resistance. We developed a protein network centered on the epidermal growth factor receptor (EGFR), which is a validated cancer therapeutic target, and used siRNA screening to comparatively probe this network for proteins that regulate the effectiveness of both EGFR-targeted agents and nonspecific cytotoxic agents. We identified subnetworks of proteins influencing resistance, with putative resistance determinants enriched among proteins that interacted with proteins at the core of the network. We found that EGFR antagonists and clinically relevant drugs targeting proteins connected in the EGFR network, such as the kinases protein kinase C or Aurora kinase A, or the transcriptional regulator STAT3, synergized to reduce cell viability and tumor size, suggesting the potential for a direct path to clinical exploitation. Such a focused approach can potentially improve the coherent design of combination cancer therapies.
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影响因子：
14.9
作者：
Jensen LJ;Kuhn M;Stark M;Chaffron S;Creevey C;Muller J;Doerks T;Julien P;Roth A;Simonovic M;Bork P;von Mering C
通讯作者：
von Mering C
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
7.3
作者：
Fan QW;Cheng C;Knight ZA;Haas-Kogan D;Stokoe D;James CD;McCormick F;Shokat KM;Weiss WA
通讯作者：
Weiss WA
影响因子：
5.8
作者：
Hopper-Borge EA;Nasto RE;Ratushny V;Weiner LM;Golemis EA;Astsaturov I
通讯作者：
Astsaturov I