AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases:: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models
AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases:: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models
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DOI：
10.1158/1535-7163.mct-07-0231
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发表时间：
2007-08-01
影响因子：
5.7
通讯作者：
Smith, Paul D.
中科院分区：
文献类型：
--
作者：
Davies, Barry R.;Logie, Armelle;Smith, Paul D.
细胞外信号调节激酶1/2（ERK1/2）丝裂原活化蛋白激酶（MAPK）信号通路在人类癌症中的组成性激活通常与BRAF或RAS的突变激活有关。MAPK/ERK激酶1/2位于RAS和BRAF的下游，是ERK1/2唯一公认的激活因子，这使它们成为治疗干预的有吸引力的靶点。AZD6244（ARRY - 142886）是一种强效、选择性且非ATP竞争性的MAPK/ERK激酶1/2抑制剂。对一组肿瘤细胞系进行体外细胞活力抑制筛选发现，携带BRAF或RAS突变的细胞系更有可能对AZD6244敏感。研究了AZD6244在体内抑制肿瘤生长的机制。以25mg/kg的剂量每日两次（bd）长期给药AZD6244可抑制Colo - 205、Calu - 6和SW - 620异种移植物的生长，而单次急性给药则可显著抑制ERK1/2的磷酸化。在Colo - 205和Calu - 6中检测到凋亡标志物裂解的半胱天冬酶 - 3增加，但在SW - 620肿瘤中未检测到，不过在SW - 620肿瘤中检测到细胞增殖显著减少。长期给予AZD6244可诱导SW - 620肿瘤的形态发生变化，使其呈现出更分化的表型。在携带SW - 620异种移植物的小鼠中评估了AZD6244与细胞毒性药物联合使用的潜力。以可耐受的剂量使用AZD6244与伊立替康或多西他赛联合治疗，相对于单独使用任何一种药物，抗肿瘤疗效显著增强。这些结果表明，AZD6244具有抑制增殖、诱导凋亡和分化的潜力，但不同异种移植物的反应有所不同。此外，将AZD6244与细胞毒性药物伊立替康或多西他赛联合使用可提高抗肿瘤疗效。
Constitutive activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway in human cancers is often associated with mutational activation of BRAF or RAS. MAPK/ERK kinase 1/2 kinases lie downstream of RAS and BRAF and are the only acknowledged activators of ERK1/2, making them attractive targets for therapeutic intervention. AZD6244 (ARRY-142886) is a potent, selective, and ATP-uncompetitive inhibitor of MAPK/ERK kinase 1/2. In vitro cell viability inhibition screening of a tumor cell line panel found that lines harboring BRAF or RAS mutations were more likely to be sensitive to AZD6244. The in vivo mechanisms by which AZD6244 inhibits tumor growth were investigated. Chronic dosing with 25 mg/kg AZD6244 bd resulted in suppression of growth of Colo-205, Calu-6, and SW-620 xenografts, whereas an acute dose resulted in significant inhibition of ERK1/2 phosphorylation. Increased cleaved caspase-3, a marker of apoptosis, was detected in Colo-205 and Calu-6 but not in SW-620 tumors where a significant decrease in cell proliferation was detected. Chronic dosing of AZD6244 induced a morphologic change in SW-620 tumors to a more differentiated phenotype. The potential of AZD 44 in combination with cytotoxic drugs was evaluated in mice bearing SW-620 xenografts. Treatment with tolerated doses of AZD6244 and either irinotecan or docetaxel resulted in significantly enhanced antitumor efficacy relative to that of either agent alone. These results indicate that AZD6244 has potential to inhibit proliferation and induce apoptosis and differentiation, but the response varies between different xenografts. Moreover, enhanced antitumor efficacy can be obtained by combining AZD6244 with the cytotoxic drugs irinotecan or docetaxel.