K-Ras mutation-mediated IGF-1-induced feedback ERK activation contributes to the rapalog resistance in pancreatic ductal adenocarcinomas

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• 作者：Feng Wei^a ; ^b ; Yan Liu^b ; Anita C. Bellail^b ; Jeffrey J. Olson^b ; Shi-Yong Sun^b ; Guoyue Lu^a ; Lijuan Ding^a ; Changji Yuan^a ; Guangyi Wang^a ; ^{wgymd@sina.com} ; Chunhai Hao^b ; ^{chao@emory.edu}
• 关键词：K-Ras ; mTORC1 ; Rapalog ; ERK ; Pancreatic cancer
• 出版年：2012
• 期刊代码：44_03043835
• 类别：med
• 出版时间：1 September, 2012
• 卷：322
• 期：1
• 页码：58-69
• 文件大小：2369 K

摘要

Mammalian target of rapamycin complex 1 (mTORC1) is frequently activated in human cancers; however, clinical trials of rapalog (the mTORC1 inhibitors) have shown that pancreatic ductal adenocarcinomas (PDACs) resist to the treatment. Rapalog treatment activated the extracellular signal-regulated kinase (ERK) pathway in K-Ras mt PDAC cells. K-Ras knockdown abolished the insulin-like growth factor-1 (IGF-1)-induced ERK pathway in the K-Ras mt PDAC cells and enhanced the therapeutic efficacy of everolimus in treating K-Ras mt PDAC cells-derived mouse xenografts. The results indicate that targeting of K-Ras mutation may lead to the development of therapies that overcome rapalog resistance in PDAC.