PMID- 24939055
OWN - NLM
STAT- MEDLINE
DCOM- 20140826
LR  - 20211021
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Print)
IS  - 0392-9078 (Linking)
VI  - 33
IP  - 1
DP  - 2014 Jun 17
TI  - Antitumor activity of selective MEK1/2 inhibitor AZD6244 in combination with 
      PI3K/mTOR inhibitor BEZ235 in gefitinib-resistant NSCLC xenograft models.
PG  - 52
LID - 10.1186/1756-9966-33-52 [doi]
AB  - PURPOSE: Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) 
      gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients 
      become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, 
      MET amplification, and KRAS mutation, thereafter relapsing. AZD6244 is a potent, 
      selective, and orally available MEK1/2 inhibitor. In this study, we evaluated the 
      therapeutic efficacy of AZD6244 alone or with BEZ235, an orally available potent 
      inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of 
      rapamycin (mTOR), in gefitinib-resistant non-small cell lung carcinoma (NSCLC) 
      models. EXPERIMENTAL DESIGN: NCI-H1975 with EGFR-T790M mutation, NCI-H1993 with 
      MET amplification and NCI-H460 with KRAS/PIK3CA mutation human NSCLC cells were 
      subcutaneous injected into the athymic nude mice respectively. Mice were randomly 
      assigned to treatment with AZD6244, BEZ235, AZD6244 plus BEZ235, or control for 
      3 weeks, then all mice were sacrificed and tumor tissues were subjected to 
      western blot analyses and immunohistochemical staining. RESULTS: AZD6244 could 
      inhibit the tumor growth of NCI-H1993, but slightly inhibit the tumor growth of 
      NCI-1975 and NCI-H460. Combining AZD6244 with BEZ235 markedly enhanced their 
      antitumor effects and without any marked adverse events. Western blot analysis 
      and immunohistochemical staining revealed that AZD6244 alone reduced ERK1/2 
      phosphorylation, angiogenesis, and tumor cell proliferation. Moreover, MEK1/2 
      inhibition resulted in decreased AKT phosphorylation in NCI-H1993 tumor model. 
      BEZ235 also inhibited AKT phosphorylation as well as their downstream molecules 
      in all three tumor models. The antiangiogenic effects were substantially enhanced 
      when the agents were combined, which may due to the reduced expression of matrix 
      metallopeptidase-9 in tumor tissues (MMP-9). CONCLUSIONS: In this study, we 
      evaluated therapy directed against MEK and PI3K/mTOR in distinct 
      gefitinib-resistant NSCLC xenograft models. Combining AZD6244 with BEZ235 
      enhanced their antitumor and antiangiogenic effects. We concluded that the 
      combination of a selective MEK inhibitor and a PI3K/mTOR inhibitor was effective 
      in suppressing the growth of gefitinib-resistant tumors caused by EGFR T790M 
      mutation, MET amplification, and KRAS/PIK3CA mutation. This new therapeutic 
      strategy may be a practical approach in the treatment of these patients.
FAU - Qu, Yiqing
AU  - Qu Y
AD  - Department of Respiratory medicine, Qilu Hospital of Shandong University, 107 
      Wenhuaxi Road, Jinan 250012, China. yiqing_qu@126.com.
FAU - Wu, Xiuxiu
AU  - Wu X
FAU - Yin, Yunhong
AU  - Yin Y
FAU - Yang, Yan
AU  - Yang Y
FAU - Ma, Dedong
AU  - Ma D
FAU - Li, Hao
AU  - Li H
LA  - eng
PT  - Journal Article
DEP - 20140617
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - 0 (AZD 6244)
RN  - 0 (Benzimidazoles)
RN  - 0 (Imidazoles)
RN  - 0 (Ki-67 Antigen)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Platelet Endothelial Cell Adhesion Molecule-1)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (Quinolines)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 3.4.22.- (Caspases)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Animals
MH  - Benzimidazoles/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/enzymology/pathology
MH  - Caspases/metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Drug Resistance, Neoplasm
MH  - Drug Synergism
MH  - Female
MH  - Gefitinib
MH  - Humans
MH  - Imidazoles/*pharmacology
MH  - Ki-67 Antigen/metabolism
MH  - Lung Neoplasms/*drug therapy/enzymology/pathology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Platelet Endothelial Cell Adhesion Molecule-1/metabolism
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Protein Kinases/metabolism
MH  - Quinazolines/*pharmacology
MH  - Quinolines/*pharmacology
MH  - Signal Transduction
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
PMC - PMC4074836
EDAT- 2014/06/19 06:00
MHDA- 2014/08/27 06:00
PMCR- 2014/06/17
CRDT- 2014/06/19 06:00
PHST- 2014/05/23 00:00 [received]
PHST- 2014/06/02 00:00 [accepted]
PHST- 2014/06/19 06:00 [entrez]
PHST- 2014/06/19 06:00 [pubmed]
PHST- 2014/08/27 06:00 [medline]
PHST- 2014/06/17 00:00 [pmc-release]
AID - 1756-9966-33-52 [pii]
AID - 10.1186/1756-9966-33-52 [doi]
PST - epublish
SO  - J Exp Clin Cancer Res. 2014 Jun 17;33(1):52. doi: 10.1186/1756-9966-33-52.