PMID- 24405594
OWN - NLM
STAT- MEDLINE
DCOM- 20140711
LR  - 20211203
IS  - 1007-8738 (Print)
IS  - 1007-8738 (Linking)
VI  - 30
IP  - 1
DP  - 2014 Jan
TI  - [Mechanism underlying pancreatic cancer cell resistance to mTOR inhibitor RAD001 
      via c-Raf/ERK1/2 activation].
PG  - 23-7
AB  - OBJECTIVE: To investigate the molecular mechanism of pancreatic cancer cell 
      resistance to mammalian target of rapamycin (mTOR) inhibitor RAD001, and explore 
      a feasible therapeutic strategy to overcome the resistance in patients with 
      pancreatic cancer. METHODS: Western blotting was conducted to find out whether 
      RAD001 induced c-Raf-ERK feedback activation and to identify whether RAD001 in 
      combination with c-Raf inhibitor sorafenib could effectively block the feedback 
      activation of c-Raf and downstream proteins. Sulphorhodamine B (SRB) colorimetric 
      assay and colony formation were used to detect the effect of the combination 
      treatment on cell growth and proliferation; finally, the effect on mouse 
      subcutaneous xenografts was examined to confirm the efficacy of the combination 
      treatment in vivo. RESULTS: RAD001 effectively inhibited the expressions of 
      mTORC1 and its downstream proteins, and induced the feedback activation of c-Raf. 
      Whereas, RAD001 combined with c-Raf inhibitor sorafenib eliminated RAD001-induced 
      activation of c-Raf-ERK pathway and reversed pancreatic cancer cell resistance to 
      RAD001; compared with the RAD001 alone, sorafenib had a synergistical inhibitory 
      effect with RAD001. And the tumor growth inhibitory effect of the combination was 
      also proved in mouse subcutaneous xenografts in vivo. CONCLUSION: RAD001-induced 
      c-Raf-ERK feedback activation contributes to pancreatic cancer cell resistance to 
      RAD001. Targeting of c-Raf may improve the therapeutic efficacy of RAD001 in 
      patients with pancreatic cancer.
FAU - Wei, Feng
AU  - Wei F
AD  - Department of Hepatobiliary & Pancreas Surgery, First Hospital, Jilin University, 
      Changchun 130021, China.
FAU - Zhang, Ping
AU  - Zhang P
FAU - Qi, Jun
AU  - Qi J
FAU - Wang, Meng
AU  - Wang M
FAU - Wang, Guangyi
AU  - Wang G
LA  - chi
PT  - Journal Article
PL  - China
TA  - Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi
JT  - Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular 
      immunology
JID - 101139110
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Enzyme Activation/drug effects
MH  - Everolimus
MH  - Humans
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 1/*metabolism
MH  - Mitogen-Activated Protein Kinase 3/*metabolism
MH  - Neoplasm Metastasis
MH  - Pancreatic Neoplasms/*pathology
MH  - Proto-Oncogene Proteins c-raf/*metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*analogs & derivatives/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
EDAT- 2014/01/11 06:00
MHDA- 2014/07/12 06:00
CRDT- 2014/01/11 06:00
PHST- 2014/01/11 06:00 [entrez]
PHST- 2014/01/11 06:00 [pubmed]
PHST- 2014/07/12 06:00 [medline]
PST - ppublish
SO  - Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2014 Jan;30(1):23-7.