title: Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752.
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.
authors.affiliation: Cancer Center and Department of Pathology, Molecular Pathology Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Gromoslaw A
authors.initials: GA
authors.lastname: Smolen
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sordella
authors.forename: Beth
authors.initials: B
authors.lastname: Muir
authors.forename: Gayatry
authors.initials: G
authors.lastname: Mohapatra
authors.forename: Anne
authors.initials: A
authors.lastname: Barmettler
authors.forename: Heidi
authors.initials: H
authors.lastname: Archibald
authors.forename: Woo J
authors.initials: WJ
authors.lastname: Kim
authors.forename: Ross A
authors.initials: RA
authors.lastname: Okimoto
authors.forename: Daphne W
authors.initials: DW
authors.lastname: Bell
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005784:Gene Amplification; D005820:Genetic Testing; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000235:genetics*; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D013450:Sulfones; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met