Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 7, Pages 2316-2321Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0508776103
Keywords
gene amplification; molecular marker; oncogene addiction; targeted therapy
Categories
Funding
- NCI NIH HHS [F32 CA117737] Funding Source: Medline
- PHS HHS [P01 95281] Funding Source: Medline
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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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