Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)
Enhanced Apoptosis and Tumor Growth Suppression Elicited by Combination of MEK (Selumetinib) and mTOR Kinase Inhibitors (AZD8055)
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DOI：
10.1158/0008-5472.can-11-1780
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发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Smith, Paul D.
中科院分区：
文献类型：
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作者：
Holt, Sarah V.;Logie, Armelle;Smith, Paul D.
丝裂原活化蛋白激酶（MAPK）和磷酸肌醇3-激酶/AKT信号通路在癌症的多个节点（包括mTOR复合物）相互作用，这表明冗余的可能性增加，并且对单一通路抑制的任何治疗效果具有先天抗性。在这项研究中，我们研究了MAPK细胞外信号调节激酶（MEK）1/2抑制剂selumetinib（AZD 6244）与mTORC 1和mTORC 2双重抑制剂（AZD 8055）联合治疗的疗效。在人肺腺癌（非小细胞肺癌）和结直肠癌的裸鼠异种移植模型中同时给药耐受良好，并且相对于各自的单药治疗产生了增加的抗肿瘤疗效。药效学分析记录了与来自组合组的肿瘤组织中的细胞凋亡和Bim表达增加相关的相互途径抑制，其中还调节了处于MEK功能控制下的关键基因如DUSP 6。我们的工作为在临床试验中将司美替尼联合收割机与AZD 8055联合作为一种有吸引力的治疗策略提供了强有力的理论依据。Cancer Res; 72（7）; 1804-13. (C)2012年AACR。
The mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/AKT signaling pathways interact at multiple nodes in cancer, including at mTOR complexes, suggesting an increased likelihood of redundancy and innate resistance to any therapeutic effects of single pathway inhibition. In this study, we investigated the therapeutic effects of combining the MAPK extracellular signal-regulated kinase (MEK) 1/2 inhibitor selumetinib (AZD6244) with the dual mTORC1 and mTORC2 inhibitor (AZD8055). Concurrent dosing in nude mouse xenograft models of human lung adenocarcinoma (non-small cell lung cancers) and colorectal carcinoma was well tolerated and produced increased antitumor efficacy relative to the respective monotherapies. Pharmacodynamic analysis documented reciprocal pathway inhibition associated with increased apoptosis and Bim expression in tumor tissue from the combination group, where key genes such as DUSP6 that are under MEK functional control were also modulated. Our work offers a strong rationale to combine selumetinib and AZD8055 in clinical trials as an attractive therapeutic strategy. Cancer Res; 72(7); 1804-13. (C) 2012AACR.