An in vivo C. elegans model system for screening EGFR-inhibiting anti-cancer drugs.
An in vivo C. elegans model system for screening EGFR-inhibiting anti-cancer drugs.
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DOI：
10.1371/journal.pone.0042441
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shim J
中科院分区：
文献类型：
--
作者：
Bae YK;Sung JY;Kim YN;Kim S;Hong KM;Kim HT;Choi MS;Kwon JY;Shim J
表皮生长因子受体（EGFR）是公认的癌症治疗靶点。 EGFR酪氨酸激酶（TK）抑制剂，例如吉非替尼和厄洛替尼，已被开发为抗癌药物。尽管具有激活 EGFR 突变 L858R 的非小细胞肺癌对吉非替尼和厄洛替尼反应良好，但具有双重突变 EGFR T790M-L858R 的肿瘤会对这些药物产生耐药性。秀丽隐杆线虫 EGFR 同源物 LET-23 及其下游信号通路已被广泛研究，以深入了解从秀丽隐杆线虫到人类的保守调节机制。为了开发针对特定 EGFR 突变体的潜在癌症药物的体内筛选系统，我们表达了三种 LET-23 嵌合体，其中 TK 结构域被人类野生型 TK 结构域 (LET-23::hEGFR-TK)、具有 L858R 突变的 TK 结构域 (LET-23::hEGFR-TK[L858R]) 或具有 L858R 突变的 TK 结构域取代。 使用let-23启动子在秀丽隐杆线虫外阴细胞中进行T790M-L858R突变（LET-23::hEGFR-TK[T790M-L858R]）。野生型 hEGFR-TK 嵌合蛋白挽救了 let-23 突变体表型，激活突变体 hEGFR-TK 嵌合体在野生型秀丽隐杆线虫背景中诱导多外阴 (Muv) 表型。抗癌药物吉非替尼和厄洛替尼抑制表达 LET-23::hEGFR-TK[L858R] 的转基因动物中的 Muv 表型，但不抑制 LET-23::hEGFR-TK[T790M-L858R] 转基因动物中的 Muv 表型。作为试点筛选，对 8,960 种小化学品进行了 Muv 抑制测试，AG1478（一种 EGFR-TK 抑制剂）和 U0126（一种 MEK 抑制剂）被确定为 EGFR 介导的生物功能的潜在抑制剂。总之，表达嵌合 LET-23::hEGFR-TK 蛋白的转基因线虫是一种模型系统，可用于新抗癌药物的突变特异性筛选。
The epidermal growth factor receptor (EGFR) is a well-established target for cancer treatment. EGFR tyrosine kinase (TK) inhibitors, such as gefinitib and erlotinib, have been developed as anti-cancer drugs. Although non-small cell lung carcinoma with an activating EGFR mutation, L858R, responds well to gefinitib and erlotinib, tumors with a doubly mutated EGFR, T790M-L858R, acquire resistance to these drugs. The C. elegans EGFR homolog LET-23 and its downstream signaling pathway have been studied extensively to provide insight into regulatory mechanisms conserved from C. elegans to humans. To develop an in vivo screening system for potential cancer drugs targeting specific EGFR mutants, we expressed three LET-23 chimeras in which the TK domain was replaced with either the human wild-type TK domain (LET-23::hEGFR-TK), a TK domain with the L858R mutation (LET-23::hEGFR-TK[L858R]), or a TK domain with the T790M-L858R mutations (LET-23::hEGFR-TK[T790M-L858R]) in C. elegans vulval cells using the let-23 promoter. The wild-type hEGFR-TK chimeric protein rescued the let-23 mutant phenotype, and the activating mutant hEGFR-TK chimeras induced a multivulva (Muv) phenotype in a wild-type C. elegans background. The anti-cancer drugs gefitinib and erlotinib suppressed the Muv phenotype in LET-23::hEGFR-TK[L858R]-expressing transgenic animals, but not in LET-23::hEGFR-TK[T790M-L858R] transgenic animals. As a pilot screen, 8,960 small chemicals were tested for Muv suppression, and AG1478 (an EGFR-TK inhibitor) and U0126 (a MEK inhibitor) were identified as potential inhibitors of EGFR-mediated biological function. In conclusion, transgenic C. elegans expressing chimeric LET-23::hEGFR-TK proteins are a model system that can be used in mutation-specific screens for new anti-cancer drugs.
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影响因子：
64.5
作者：
Inoue, T;Oz, HS;Sternberg, PW
通讯作者：
Sternberg, PW
影响因子：
50.5
作者：
Cappuzzo, F.;Toschi, L.;Hirsch, F. R.
通讯作者：
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影响因子：
4.7
作者：
Artal-Sanz, Marto;de Jong, Liesbeth;Tavernarakis, Nektarios
通讯作者：
Tavernarakis, Nektarios
DOI：
10.1073/pnas.0502860102
发表时间：
2005-05-24
影响因子：
11.1
作者：
Kwak, EL;Sordella, R;Haber, DA
通讯作者：
Haber, DA
DOI：
10.1016/j.vascn.2004.04.002
发表时间：
2004-11-01
影响因子：
1.9
作者：
Dengg, Marlene;van Meel, Jacques C. A.
通讯作者：
van Meel, Jacques C. A.