Blocking the PI3K pathway enhances the efficacy of ALK-targeted therapy in EML4-ALK-positive nonsmall-cell lung cancer

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• 作者：Lin Yang (1)
  Guangchao Li (2)
  Likun Zhao (2)
  Fei Pan (3)
  Jiankun Qiang (4)
  Siqi Han (5)
  
• 关键词：Nonsmall ; cell lung cancer ; EML4 ; ALK ; PI3K pathway ; Combination therapy
• 刊名：Tumor Biology
• 出版年：2014
• 出版时间：October 2014
• 年：2014
• 卷：35
• 期：10
• 页码：9759-9767
• 全文大小：1,323 KB
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• 作者单位：Lin Yang (1)
  Guangchao Li (2)
  Likun Zhao (2)
  Fei Pan (3)
  Jiankun Qiang (4)
  Siqi Han (5)
  
  1. Department of Clinical Laboratory, Hubei Maternal and Child Health Hospital, Wuhan, 430070, China
  2. School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China
  3. PLA General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing, 100853, China
  4. School of Biology and Basic Medical Sciences, Soochow University, Suzhou, 215006, China
  5. Department of Medical Oncology, Jinling Hospital, 305 Zhongshan North Road, Nanjing, 210002, China
  
• ISSN：1423-0380

文摘

Targeted therapy based on ALK tyrosine kinase inhibitors (ALK-TKIs) has made significant achievements in individuals with EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion positive nonsmall-cell lung cancer (NSCLC). However, a high fraction of patients receive inferior clinical response to such treatment in the initial therapy, and the exact mechanisms underlying this process need to be further investigated. In this study, we revealed a persistently activated PI3K/AKT signaling that mediates the drug ineffectiveness. We found that genetic or pharmacological inhibition of ALK markedly abrogated phosphorylated STAT3 and ERK, but it failed to suppress AKT activity or induce apoptosis, in EML4-ALK-positive H2228 cells. Furthermore, targeted RNA interference of PI3K pathway components restored sensitivity to TAE684 treatment at least partially due to increased apoptosis. Combined TAE684 with PI3K inhibitor synergistically inhibited the proliferation of EML4-ALK-positive cells in vitro and significantly suppressed the growth of H2228 xenografts in vivo, suggesting the potential clinical application of such combinatorial therapy regimens in patients with EML4-ALK positive lung cancer.