PMID- 18381447
OWN - NLM
STAT- MEDLINE
DCOM- 20080425
LR  - 20250214
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 7
DP  - 2008 Apr 1
TI  - Epithelial-to-mesenchymal transition and integrin-linked kinase mediate 
      sensitivity to epidermal growth factor receptor inhibition in human hepatoma 
      cells.
PG  - 2391-9
LID - 10.1158/0008-5472.CAN-07-2460 [doi]
AB  - Hepatocellular carcinoma (HCC) is associated with a poor prognosis due to late 
      diagnoses and a lack of effective treatment options. Epidermal growth factor 
      receptor (EGFR)-targeted therapies have been effective in other cancers. However, 
      erlotinib and cetuximab have shown only modest efficacy in clinical trials of 
      HCC. We examined epithelial-to-mesenchymal transition (EMT) as a determinant of 
      sensitivity of HCC to EGFR inhibitors. A panel of 12 human hepatoma cell lines 
      were classified as epithelial or mesenchymal based on their expression of 
      E-cadherin and vimentin. The resulting classification correlated with a previous 
      microarray analysis of human hepatoma cell lines whereby the mesenchymal cell 
      lines were shown to have increased expression of genes involved in metastasis and 
      invasion. Sensitivity to erlotinib, gefitinib, and cetuximab was assessed and the 
      epithelial cell lines were found to be significantly more susceptible to all 
      three agents. Analysis of the EGFR pathway showed that EMT status was independent 
      of EGFR expression or downstream extracellular signal-regulated kinase activation 
      and only the epithelial cell lines expressed ErbB3. Interestingly, mesenchymal 
      cells resistant to EGFR inhibitors had increased AKT and signal transducer and 
      activator of transcription-3 activation through elevated expression of 
      integrin-linked kinase (ILK). Mesenchymal cell lines were therefore 
      experimentally transformed with kinase-inactive ILK (KI-ILK) with a resulting 
      decrease in ILK activity and activation of AKT. KI-ILK transformants showed 
      increased sensitivity to EGFR inhibitors both in vitro and in an in vivo 
      xenograft model. These data suggest that EMT predicts HCC sensitivity to 
      EGFR-targeted therapies and that ILK is a novel target to overcome HCC resistance 
      to EGFR inhibition.
FAU - Fuchs, Bryan C
AU  - Fuchs BC
AD  - Division of Surgical Oncology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, MA 02114, USA.
FAU - Fujii, Tsutomu
AU  - Fujii T
FAU - Dorfman, Jon D
AU  - Dorfman JD
FAU - Goodwin, Jonathan M
AU  - Goodwin JM
FAU - Zhu, Andrew X
AU  - Zhu AX
FAU - Lanuti, Michael
AU  - Lanuti M
FAU - Tanabe, Kenneth K
AU  - Tanabe KK
LA  - eng
GR  - 2R01CA076183/CA/NCI NIH HHS/United States
GR  - 5T32CA009535/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Cadherins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Vimentin)
RN  - 67763-97-7 (Insulin-Like Growth Factor II)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.1.- (integrin-linked kinase)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - PQX0D8J21J (Cetuximab)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Cadherins/biosynthesis
MH  - Carcinoma, Hepatocellular/drug therapy/*enzymology/*pathology
MH  - Cell Line, Tumor
MH  - Cetuximab
MH  - Enzyme Activation
MH  - Epithelial Cells/drug effects/enzymology/pathology
MH  - ErbB Receptors/*antagonists & inhibitors
MH  - Erlotinib Hydrochloride
MH  - Gefitinib
MH  - Humans
MH  - Insulin-Like Growth Factor II/metabolism
MH  - Liver Neoplasms/drug therapy/*enzymology/*pathology
MH  - Mesoderm/drug effects/enzymology/pathology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein Serine-Threonine Kinases/antagonists & 
      inhibitors/biosynthesis/*metabolism
MH  - Proto-Oncogene Proteins c-akt/biosynthesis
MH  - Quinazolines/pharmacology
MH  - Receptor, IGF Type 1/metabolism
MH  - STAT3 Transcription Factor/biosynthesis
MH  - Vimentin/biosynthesis
EDAT- 2008/04/03 09:00
MHDA- 2008/04/26 09:00
CRDT- 2008/04/03 09:00
PHST- 2008/04/03 09:00 [pubmed]
PHST- 2008/04/26 09:00 [medline]
PHST- 2008/04/03 09:00 [entrez]
AID - 68/7/2391 [pii]
AID - 10.1158/0008-5472.CAN-07-2460 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Apr 1;68(7):2391-9. doi: 10.1158/0008-5472.CAN-07-2460.