Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752

Smolen, G. A., Sordella, R., Muir, B., Mohapatra, G., Barmettler, A., Archibald, H., Kim, W. J., Okimoto, R. A., Bell, D. W., Sgroi, D. C., Christensen, J. G., Settleman, J., Haber, D. A. (February 2006) Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. Proceedings of the National Academy of Sciences of the United States of America, 103 (7). pp. 2316-21. ISSN 0027-8424

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URL: http://www.ncbi.nlm.nih.gov/pubmed/16461907
DOI: 10.1073/pnas.0508776103

Abstract

The success of molecular targeted therapy in cancer may depend on the selection of appropriate tumor types whose survival depends on the drug target, so-called "oncogene addiction." Preclinical approaches to defining drug-responsive subsets are needed if initial clinical trials are to be directed at the most susceptible patient population. Here, we show that gastric cancer cells with high-level stable chromosomal amplification of the growth factor receptor MET are extraordinarily susceptible to the selective inhibitor PHA-665752. Although MET activation has primarily been linked with tumor cell migration and invasiveness, the amplified wild-type MET in these cells is constitutively activated, and its continued signaling is required for cell survival. Treatment with PHA-665752 triggers massive apoptosis in 5 of 5 gastric cancer cell lines with MET amplification but in 0 of 12 without increased gene copy numbers (P = 0.00016). MET amplification may thus identify a subset of epithelial cancers that are uniquely sensitive to disruption of this pathway and define a patient group that is appropriate for clinical trials of targeted therapy using MET inhibitors.

Item Type: Paper
Uncontrolled Keywords: Antineoplastic Agents pharmacology Apoptosis Cell Line Tumor Cell Movement Drug Resistance, Neoplasm genetics Gene Amplification Genetic Screening Humans Indoles pharmacology Protein Tyrosine Kinases antagonists & inhibitors Proto-Oncogene Proteins genetics Receptors, Growth Factor genetics Stomach Neoplasms enzymology genetics Sulfones/ pharmacology Tumor Markers, Biological genetics
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
therapies
diseases & disorders > cancer > drugs and therapies > chemoresistance
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
diseases & disorders > cancer > cancer types > stomach cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Sordella lab
Depositing User: CSHL Librarian
Date: 14 February 2006
Date Deposited: 08 Dec 2011 15:59
Last Modified: 11 Jan 2018 16:07
PMCID: PMC1413705
Related URLs:
URI: https://repository.cshl.edu/id/eprint/22903

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