PMID- 22941374
OWN - NLM
STAT- MEDLINE
DCOM- 20130110
LR  - 20181202
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 70
IP  - 5
DP  - 2012 Nov
TI  - Everolimus synergizes with gefitinib in non-small-cell lung cancer cell lines 
      resistant to epidermal growth factor receptor tyrosine kinase inhibitors.
PG  - 707-16
LID - 10.1007/s00280-012-1946-3 [doi]
AB  - PURPOSE: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) 
      therapy is considered as one of the most important treatments for patients with 
      advanced non-small-cell lung cancer (NSCLC). However, not all patients benefit 
      from this therapy because of primary or acquired resistance, both of which are 
      usually caused by the activation of alternative signaling pathways. Thus, a 
      combination of different signaling pathway inhibitors is a promising strategy. We 
      used the mammalian target of rapamycin (mTOR) inhibitor everolimus in combination 
      with gefitinib in NSCLC cell lines to analyze the efficacy of this combination 
      regimen and the underlying molecular mechanism. METHODS: Acquired 
      gefitinib-resistant cell lines, together with EGFR wild-type and mutant primary 
      gefitinib-resistant NSCLC cell lines, were treated with everolimus alone, 
      gefitinib alone, or the combination of the two drugs, and the effects were 
      evaluated using cell proliferation assays. The effects of everolimus and 
      gefitinib on the EGFR pathway in NSCLC cell lines were determined by Western blot 
      analysis. RESULTS: Combined treatment resulted in synergistic antitumor effects 
      in gefitinib-resistant cells A549 and H1975. The combination index (CI) of cells 
      increased with increasing dose of everolimus. Everolimus demonstrated no apparent 
      inhibition of phosphorylated Akt (p-Akt) and phosphorylated p44/42 MAPK (p-MAPK) 
      in H1650 cells. Additionally, in gefitinib-resistant cell lines, the combination 
      of gefitinib and everolimus not only showed stronger inhibition of phosphorylated 
      mTOR and phosphorylated p70S6K expression than either drug alone but also reduced 
      the levels of p-Akt and p-MAPK in both cell lines. CONCLUSIONS: Our data showed 
      that the combination of everolimus and gefitinib exhibits dose-dependent 
      synergism in primary and acquired gefitinib-resistant NSCLC cells. Thus, a 
      preclinical rationale exists for the use of everolimus to enhance the efficacy of 
      gefitinib in EGFR-TKI-resistant patients with NSCLC.
FAU - Dong, Song
AU  - Dong S
AD  - Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangdong Academy of 
      Medical Sciences, Guangzhou, China.
FAU - Zhang, Xu-Chao
AU  - Zhang XC
FAU - Cheng, Hua
AU  - Cheng H
FAU - Zhu, Jian-Quan
AU  - Zhu JQ
FAU - Chen, Zhi-Hong
AU  - Chen ZH
FAU - Zhang, Yi-Fang
AU  - Zhang YF
FAU - Xie, Zhi
AU  - Xie Z
FAU - Wu, Yi-Long
AU  - Wu YL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120902
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - S65743JHBS (Gefitinib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & 
      dosage/*therapeutic use
MH  - Blotting, Western
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy/pathology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Resistance, Neoplasm
MH  - Drug Synergism
MH  - ErbB Receptors/antagonists & inhibitors
MH  - Everolimus
MH  - Gefitinib
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/pathology
MH  - Protein Kinase Inhibitors/pharmacology/therapeutic use
MH  - Quinazolines/administration & dosage/*pharmacology
MH  - Signal Transduction
MH  - Sirolimus/administration & dosage/*analogs & derivatives/pharmacology
EDAT- 2012/09/04 06:00
MHDA- 2013/01/11 06:00
CRDT- 2012/09/04 06:00
PHST- 2012/04/17 00:00 [received]
PHST- 2012/07/27 00:00 [accepted]
PHST- 2012/09/04 06:00 [entrez]
PHST- 2012/09/04 06:00 [pubmed]
PHST- 2013/01/11 06:00 [medline]
AID - 10.1007/s00280-012-1946-3 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2012 Nov;70(5):707-16. doi: 
      10.1007/s00280-012-1946-3. Epub 2012 Sep 2.