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Cellular, Molecular, and Tumor Biology 37: Tobacco-related Malignancies: Tumors of the Head and Neck and Lung

c-MET expression/activation, functions, and mutations in non-small cell lung cancer

Patrick C. Ma, Simha Jagadeesh, Ramasamy Jagadeeswaran, Edward A. Fox, James Christensen, Gautam Maulik, Katsuhiko Naoki, Erik Schaefer, Alan Lader, William Richards, David Sugarbaker, Matthew Meyerson and Ravi Salgia
Patrick C. Ma
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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Simha Jagadeesh
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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Ramasamy Jagadeeswaran
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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Edward A. Fox
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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James Christensen
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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Gautam Maulik
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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Katsuhiko Naoki
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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Erik Schaefer
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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Alan Lader
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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William Richards
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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David Sugarbaker
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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Matthew Meyerson
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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Ravi Salgia
The University of Chicago Medical Center, Chicago, IL, Dana-Farber Cancer Institute, Boston, MA, Pfizer, Inc., South San Francisco, CA, Biosource International, Inc., Camarillo, CA, Brigham and Women’s Hospital, HMS, Boston, MA
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DOI:  Published April 2004
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Proc Amer Assoc Cancer Res, Volume 45, 2004

Abstract

1875

c-MET is believed to be an attractive target for molecular therapeutic inhibition in cancers associated with overexpression or activating mutations of c-MET. Since non-small cell lung cancer (NSCLC) is a difficult disease to treat, we have examined the expression of c-MET in 15 NSCLC cell lines using standard immunoblotting with anti-human c-MET antibody. There was overexpression of c-MET in most of the cell lines, including A549, H1838, H2170, SW-900, H358, H1993, Calu-3, Calu-1 and H596; while SK-NES-1, SW-1573, SK-LU-1, and Calu-6 had a lower c-MET expression. H661 did not express c-MET, and H520 expressed c-MET only minimally. Utilizing standard immunoperoxidase staining technique with anti-c-MET antibody and also phosphospecific c-MET antibodies (pY1230/1234/1235 auto-phosphorylation sites; and pY1003 juxtamembrane c-Cbl binding site), we show that expression of both total c-MET and also phosphorylated activated-MET are present in various subtypes of NSCLC tumor tissues. Specifically, strong activated-MET immunoperoxidase staining was seen in the invasion fronts of the tumor tissues. Also, up to 80% or more of the various NSCLC tumor tissue subtypes, including adenocarcinoma, squamous cell, large cell, examined expressed pY1003-Met and pY1230/1234/1235-Met. Since we have recently identified novel somatic missense mutations and alternatively spliced transcripts of c-MET in SCLC, we have begun to screen for mutations of c-MET in NSCLC cell lines (n=8) and also adenocarcinoma tumor tissues (n=127). Most interestingly, preliminary analysis of the sequencing results show clustering of mutations within the Sema (semaphorin) and JM (juxtamembrane) domains; however no mutations of the tyrosine kinase domain have been identified. We have now identified two novel sema domain missense mutations, S323G and N375S, in 3 different tumor tissue samples. In addition, we found several interesting JM mutations in the various cDNA samples. These include the R988C JM mutation, simultaneous JM mutations of R988C and T1010I, and also an alternative splice form with 47 amino acid deletion of the entire exon 14 (JM domain) of c-MET. Utilizing the adenocarcinoma A549 cell line that overexpresses c-MET to study signal transduction, we further show that HGF/c-MET pathway is functional and responsive to HGF (40 ng/ml) stimulation in a time-dependent fashion, with significant HGF-induced phosphorylation of c-MET, AKT, and p70-S6K. Also, there was HGF-induced tyrosine phosphorylation of the pY1230/1234/1235 sites demonstrated with the immunofluorescent staining using the phosphospecific antibodies. c-MET appears to be an important therapeutic target in NSCLC, and inhibitory strategies developed to target the receptor tyrosine kinase would be important to improve the therapeutic outcome.

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April 2004
Volume 64, Issue 7 Supplement
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c-MET expression/activation, functions, and mutations in non-small cell lung cancer
Patrick C. Ma, Simha Jagadeesh, Ramasamy Jagadeeswaran, Edward A. Fox, James Christensen, Gautam Maulik, Katsuhiko Naoki, Erik Schaefer, Alan Lader, William Richards, David Sugarbaker, Matthew Meyerson and Ravi Salgia
Cancer Res April 1 2004 (64) (7 Supplement) 430-431;

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c-MET expression/activation, functions, and mutations in non-small cell lung cancer
Patrick C. Ma, Simha Jagadeesh, Ramasamy Jagadeeswaran, Edward A. Fox, James Christensen, Gautam Maulik, Katsuhiko Naoki, Erik Schaefer, Alan Lader, William Richards, David Sugarbaker, Matthew Meyerson and Ravi Salgia
Cancer Res April 1 2004 (64) (7 Supplement) 430-431;
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Show more Cellular, Molecular, and Tumor Biology 37: Tobacco-related Malignancies: Tumors of the Head and Neck and Lung
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