PMID- 15956968
OWN - NLM
STAT- MEDLINE
DCOM- 20050912
LR  - 20220216
IS  - 0007-0920 (Print)
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Linking)
VI  - 92
IP  - 12
DP  - 2005 Jun 20
TI  - Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL 
      mutations in renal cell carcinoma.
PG  - 2266-77
AB  - Epidermal growth factor receptor (EGFR) and tumour growth factor alpha (TGFalpha) 
      are frequently overexpressed in renal cell carcinoma (RCC) yet responses to 
      single-agent EGFR inhibitors are uncommon. Although von Hippel-Lindau (VHL) 
      mutations are predominant, RCC also develops in individuals with tuberous 
      sclerosis (TSC). Tuberous sclerosis mutations activate mammalian target of 
      rapamycin (mTOR) and biochemically resemble VHL alterations. We found that RCC 
      cell lines expressed EGFR mRNA in the near-absence of other ErbB family members. 
      Combined EGFR and mTOR inhibition synergistically impaired growth in a 
      VHL-dependent manner. Iressa blocked ERK1/2 phosphorylation specifically in 
      wt-VHL cells, whereas rapamycin inhibited phospho-RPS6 and 4E-BP1 irrespective of 
      VHL. In contrast, phospho-AKT was resistant to these agents and MYC translation 
      initiation (polysome binding) was similarly unaffected unless AKT was inhibited. 
      Primary RCCs vs cell lines contained similar amounts of phospho-ERK1/2, much 
      higher levels of ErbB-3, less phospho-AKT, and no evidence of phospho-RPS6, 
      suggesting that mTOR activity was reduced. A subset of tumours and cell lines 
      expressed elevated eIF4E in the absence of upstream activation. Despite similar 
      amounts of EGFR mRNA, cell lines (vs tumours) overexpressed EGFR protein. In the 
      paired cell lines, PRC3 and WT8, EGFR protein was elevated post-transcriptionally 
      in the VHL mutant and EGF-stimulated phosphorylation was prolonged. We propose 
      that combined EGFR and mTOR inhibitors may be useful in the subset of RCCs with 
      wt-VHL. However, apparent differences between primary tumours and cell lines 
      require further investigation.
FAU - Gemmill, R M
AU  - Gemmill RM
AD  - Division of Medical Oncology, University of Colorado at Denver and Health 
      Sciences and Cancer Centers, Mail Stop 8117, PO Box 6511, Aurora, CO 80045-0511, 
      USA. robert.gemmill@uchsc.edu
FAU - Zhou, M
AU  - Zhou M
FAU - Costa, L
AU  - Costa L
FAU - Korch, C
AU  - Korch C
FAU - Bukowski, R M
AU  - Bukowski RM
FAU - Drabkin, H A
AU  - Drabkin HA
LA  - eng
GR  - P30 CA046934/CA/NCI NIH HHS/United States
GR  - R01 CA076035/CA/NCI NIH HHS/United States
GR  - CA046934/CA/NCI NIH HHS/United States
GR  - CA76035/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinazolines)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 6.3.2.- (VHL protein, human)
RN  - S65743JHBS (Gefitinib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Carcinoma, Renal Cell/*drug therapy/metabolism
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - ErbB Receptors/biosynthesis/genetics
MH  - Gefitinib
MH  - Humans
MH  - Kidney Neoplasms/*drug therapy/metabolism
MH  - Mutation
MH  - Protein Kinases/biosynthesis/genetics
MH  - Quinazolines/pharmacology/*therapeutic use
MH  - Sirolimus/pharmacology/*therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Tumor Suppressor Proteins/*genetics
MH  - Ubiquitin-Protein Ligases/*genetics
MH  - Von Hippel-Lindau Tumor Suppressor Protein
PMC - PMC2361810
EDAT- 2005/06/16 09:00
MHDA- 2005/09/13 09:00
PMCR- 2006/06/20
CRDT- 2005/06/16 09:00
PHST- 2005/06/16 09:00 [pubmed]
PHST- 2005/09/13 09:00 [medline]
PHST- 2005/06/16 09:00 [entrez]
PHST- 2006/06/20 00:00 [pmc-release]
AID - 6602646 [pii]
AID - 10.1038/sj.bjc.6602646 [doi]
PST - ppublish
SO  - Br J Cancer. 2005 Jun 20;92(12):2266-77. doi: 10.1038/sj.bjc.6602646.