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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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.
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