Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance.
Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance.
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DOI：
10.18632/oncotarget.659
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发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Martelli AM
中科院分区：
文献类型：
--
作者：
McCubrey JA;Steelman LS;Chappell WH;Abrams SL;Franklin RA;Montalto G;Cervello M;Libra M;Candido S;Malaponte G;Mazzarino MC;Fagone P;Nicoletti F;Bäsecke J;Mijatovic S;Maksimovic-Ivanic D;Milella M;Tafuri A;Chiarini F;Evangelisti C;Cocco L;Martelli AM
Ras/Raf/MEK/ERK和PI3K/PTEN/Akt/mTOR级联信号通路通常被上游信号分子如受体酪氨酸激酶(RTK)的基因改变所激活。靶向这些途径通常是复杂的，并可能导致途径激活，这取决于上游突变的存在(例如，Raf抑制剂在野生型(WT)RAF细胞中诱导Raf激活)，而雷帕霉素可以诱导Akt激活。靶向同一通路的两个成分或两个不同的信号通路的抑制剂可能是一种更有效的方法。这篇综述将首先评估Raf、MEK、PI3K、Akt和mTOR抑制剂在临床前和临床研究中的潜在用途，然后讨论癌症如何对各种抑制剂变得不敏感以及克服这种耐药性的潜在策略。
The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance.
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DOI：
10.4161/cc.10.4.14864
发表时间：
2011-02-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
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通讯作者：
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DOI：
10.18632/aging.100273
发表时间：
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期刊：
Aging
影响因子：
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Poroshina TE
DOI：
10.18632/aging.100422
发表时间：
2011-12
期刊：
Aging
影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
5.7
作者：
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通讯作者：
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