FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML.
FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML.
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DOI：
10.1016/j.drup.2009.04.001
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发表时间：
2009-06
影响因子：
24.3
通讯作者：
Griffin, James D.
中科院分区：
文献类型：
--
作者：
Weisberg, Ellen;Barrett, Rosemary;Liu, Qingsong;Stone, Richard;Gray, Nathanael;Griffin, James D.
AML的一个有吸引力的治疗靶点是结构性激活的突变的Flt3，它在AML患者的亚群中表达，在65岁以下的患者中通常是一个不良的预后指标。目前有几种Flt3抑制剂正在进行临床研究。然而，在接受Flt3抑制剂治疗的AML患者中发现耐药的白血病原始细胞，促使人们寻找新的、结构多样化的Flt3抑制剂，这些抑制剂可以替代用于规避耐药性。在这里，我们提供了处于临床前和临床研究中的Flt3抑制剂的概述，并讨论了AML细胞对Flt3抑制剂产生耐药性的机制，以及联合治疗可能被用来克服耐药性的方法。我们讨论了如何利用主要下游信号通路之间的串扰，如PI3K/PTEN/Akt/mTOR，RAS/Raf/MEK/ERK，和JAK/STAT，通过靶向关键信号分子的选择性抑制剂，如mTOR抑制剂，HSP90抑制剂，或法尼基转移酶抑制剂，并确定那些能够与Flt3抑制剂正结合的药物，如PKC412和Sunitinib。随着与酪氨酸激酶抑制剂相关的耐药性的广泛出现，由于涉及点突变或靶蛋白基因扩增的机制，使用多靶点治疗方法具有潜在的临床益处。
An appealing therapeutic target for AML is constitutively-activated, mutant FLT3, which is expressed in a subpopulation of AML patients and is generally a poor prognostic indicator in patients under the age of 65. There are currently several FLT3 inhibitors that are undergoing clinical investigation. However, the discovery of drug-resistant leukemic blast cells in FLT3 inhibitor-treated AML patients has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to circumvent drug resistance. Here, we provide an overview of FLT3 inhibitors under preclinical and clinical investigation, and we discuss mechanisms whereby AML cells develop resistance to FLT3 inhibitors, and the ways in which combination therapy could potentially be utilized to override drug resistance. We discuss how the cross-talk between major downstream signaling pathways, such as PI3K/PTEN/Akt/mTOR, RAS/Raf/MEK/ERK, and Jak/STAT, can be exploited for therapeutic purposes by targeting key signaling molecules with selective inhibitors, such as mTOR inhibitors, HSP90 inhibitors, or farnesyltransferase inhibitors, and identifying those agents with the ability to positively combine with inhibitors of FLT3, such as PKC412 and sunitinib. With the widespread onset of drug resistance associated with tyrosine kinase inhibitors, due to mechanisms involving development of point mutations or gene amplification of target proteins, the use of a multi-targeted therapeutic approach is of potential clinical benefit.
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DOI：
10.1073/pnas.0812413106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Gajiwala, Ketan S.;Wu, Joe C.;Demetri, George D.
通讯作者：
Demetri, George D.
影响因子：
6.5
作者：
Al Shaer, Laila;Walsby, Elisabeth;Rowntree, Clare
通讯作者：
Rowntree, Clare
影响因子：
20.3
作者：
Giles, FJ;Stopeck, AT;Karp, JE
通讯作者：
Karp, JE
影响因子：
5.7
作者：
Ikezoe, Takayuki;Nishioka, Chie;Taguchi, Hirokuni
通讯作者：
Taguchi, Hirokuni
影响因子：
11.4
作者：
Horiike, S;Yokota, S;Misawa, S
通讯作者：
Misawa, S