Blockade of MEK/ERK signaling enhances sunitinib-induced growth inhibition and apoptosis of leukemia cells possessing activating mutations of the FLT3 gene
Blockade of MEK/ERK signaling enhances sunitinib-induced growth inhibition and apoptosis of leukemia cells possessing activating mutations of the FLT3 gene
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DOI：
10.1016/j.leukres.2007.09.017
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发表时间：
2008-06-01
影响因子：
2.7
通讯作者：
Yokoyama, Akihito
中科院分区：
文献类型：
--
作者：
Nishioka, Chie;Ikezoe, Takayuki;Yokoyama, Akihito
FMS样酪氨酸激酶3(Flt3)是一种细胞表面受体酪氨酸激酶。该基因的激活突变发生在近30%的急性髓细胞白血病(AML)患者中。这些突变在一定程度上导致了丝裂原活化蛋白激酶(MEK)/细胞外信号调节激酶(ERK)信号通路的激活。在本研究中，我们发现新的MEK1/2激酶抑制剂AZD6244(ARRY-142886)能有效地抑制急性双表型白血病MV4-11和急性单核细胞白血病MOLM13细胞的增殖。通过培养第2天的胸腺嘧啶核苷摄取量测定，抑制50%生长的浓度分别约为0.3和1.2mU M。Western印迹分析显示，AZD6244能有效下调MV4-11和MOLM13细胞中磷酸化ERK1/2及其下游效应蛋白p-p70S6K的表达水平。有趣的是，当AZD6244与Flt3激酶抑制剂舒尼替尼联合使用时，MV4-11和MOLM13细胞的生长抑制和凋亡都得到协同增强，并进一步下调了这些细胞中的磷酸化ERK1/2和p-p70S6K。综上所述，同时阻断Flt3和MEK信号是一种有希望的治疗策略，适用于拥有Flt3激活突变的白血病患者。(C)2007爱思唯尔有限公司。保留所有权利。
The FMS-like tyrosine kinase 3 (FLT3) is a cell surface receptor tyrosine kinase. Activating mutations of this gene occur in nearly 30% of acute myelogenous leukemia (AML) patients. These mutations, in part, result in activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. In this study, we found that AZD6244 (ARRY-142886), a novel inhibitor of MEK 1/2 kinases, effectively inhibited the proliferation of acute biphenotypic leukemia MV4-11 and acute monocytic leukemia MOLM 13 cells. The concentrations that inhibited 50% growth were approximately 0.3 and 1.2 mu M, respectively, as measured by thymidine uptake on day 2 of culture. AZD6244 potently down-regulated the levels of phospho-ERK1/2 and its downstream effector, p-p70S6K, in the MV4-11 and MOLM 13 cells as measured by Western blot analysis. Interestingly, when AZD6244 was combined with sunitinib, a FLT3 kinase inhibitor, growth inhibition and apoptosis of both MV4-11 and MOLM13 cells were synergistically enhanced in association with further down-regulation of phospho-ERK1/2 and p-p70S6K in these cells. Taken together, concomitant blockade of FLT3 and MEK signaling represents a promising treatment strategy for individuals with leukemia who possess activating mutations of FLT3. (c) 2007 Elsevier Ltd. All rights reserved.