Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs.
Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs.
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DOI：
10.1038/sj.bjc.6604269
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发表时间：
2008-03-11
影响因子：
8.8
通讯作者：
Tortora, G.
中科院分区：
文献类型：
--
作者：
Bianco, R.;Garofalo, S.;Rosa, R.;Damiano, V.;Gelardi, T.;Daniele, G.;Marciano, R.;Ciardiello, F.;Tortora, G.
由于替代信号传导的激活，单一转导途径的抑制通常是无效的。哺乳动物雷帕霉素靶蛋白（mTOR）是一种整合增殖、存活和血管生成途径的关键细胞内激酶，并与EGFR抑制剂的耐药性有关。因此，寻求mTOR阻断以在多个水平上干扰肿瘤生长。我们使用依维莫司（RAD 001）单独或与抗EGFR药物吉非替尼或西妥昔单抗联合抑制mTOR，在体外和体内对EGFR抑制剂敏感和耐药的人癌细胞系上。我们证明依维莫司对EGFR耐药癌细胞系具有活性，并部分恢复EGFR抑制剂抑制生长和存活的能力。依维莫司单独使用和与吉非替尼联合使用可降低EGFR相关信号效应物的表达和VEGF的产生，抑制内皮细胞的增殖和毛细血管形成。最后，依维莫司和吉非替尼的组合抑制GEO和GEO-GR（吉非替尼抗性）结肠癌异种移植物的生长、信号传导蛋白的活化和VEGF分泌。用依维莫司靶向mTOR通路克服了对EGFR抑制剂的耐药性，并与EGFR抑制剂产生协同作用，提供了一种有效的治疗策略，可在临床环境中进行测试。
Inhibition of a single transduction pathway is often inefficient due to activation of alternative signalling. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation, survival and angiogenic pathways and has been implicated in the resistance to EGFR inhibitors. Thus, mTOR blockade is pursued to interfere at multiple levels with tumour growth. We used everolimus (RAD001) to inhibit mTOR, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo. We demonstrated that everolimus is active against EGFR-resistant cancer cell lines and partially restores the ability of EGFR inhibitors to inhibit growth and survival. Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib. Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion. Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting.
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影响因子：
11.5
作者：
Abraham, Robert T.;Gibbons, James J.
通讯作者：
Gibbons, James J.
影响因子：
45.3
作者：
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Wen, P. Y.
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Gemmill RM;Zhou M;Costa L;Korch C;Bukowski RM;Drabkin HA
通讯作者：
Drabkin HA
影响因子：
11.5
作者：
Ciardiello, F;Bianco, R;Tortora, G
通讯作者：
Tortora, G