title: NVP-BEZ235 overcomes gefitinib-acquired resistance by down-regulating PI3K/AKT/mTOR phosphorylation.
abstract: BACKGROUND
  Patients harboring activating mutations in epidermal growth factor receptors (EGFR) are particularly sensitive to EGFR tyrosine kinase inhibitors (TKIs). However, most patients develop an acquired resistance after a period of about 10 months. This study focuses on the therapeutic effect of NVP-BEZ235, a dual inhibitor of phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR), in gefitinib-resistant non-small cell lung cancer.
  
  
  METHODS
  H1975 cell line was validated as a gefitinib-resistant cell model by the nucleotide-sequence analysis. We used the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay to detect the growth of H1975 cell line in vitro. H1975 cells' migration was detected by the migration assay. Xenograft models were used to investigate the growth of gefitinib-resistant non-small cell lung cancer in vivo. Western blot and immunohistochemical analysis were used to investigate the level of PI3K/protein kinase B(AKT)/mTOR signaling pathway proteins.
  
  
  RESULTS
  We show that NVP-BEZ235 effectively inhibited the growth of H1975 cells in vivo as well as in vitro. Similarly, H1975 cell migration was reduced by NVP-BEZ235. Further experiments revealed that NVP-BEZ235 attenuated the phosphorylation of PI3K/AKT/mTOR signaling pathway proteins.
  
  
  CONCLUSIONS
  Taken together, we suggest that NVP-BEZ235 inhibits gefitinib-resistant tumor growth by downregulating PI3K/AKT/mTOR phosphorylation.
authors: Oncology department, Xiangyang central Hospital, Xiangyang, Hubei, People's Republic of China.
authors: Zhihua
authors: Z
authors: Sun
authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors: Qiuhui
authors: Q
authors: Li
authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors: Sheng
authors: S
authors: Zhang
authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors: Jing
authors: J
authors: Chen
authors: Radiation Oncology Department, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People's Republic of China.
authors: Lili
authors: L
authors: Huang
authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors: Jinghua
authors: J
authors: Ren
authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors: Yu
authors: Y
authors: Chang
authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors: Yichen
authors: Y
authors: Liang
authors: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors: Gang
authors: G
authors: Wu
keywords: NVP-BEZ235; PI3K kinase; gefitinib-acquired resistance; mTOR