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

Gromoslaw A. Smolen, Raffaella Sordella, Beth Muir, Gayatry Mohapatra, Anne Barmettler, Heidi Archibald, Woo J. Kim, Ross A. Okimoto, Daphne W. Bell, Dennis C. Sgroi, James G. Christensen, Jeffrey Settleman, Daniel A. Haber

Research output: Contribution to journalArticle

410 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2316-2321
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number7
DOIs
StatePublished - Feb 14 2006
Externally publishedYes

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Protein-Tyrosine Kinases
Stomach Neoplasms
Neoplasms
Clinical Trials
Molecular Targeted Therapy
Gene Dosage
Growth Factor Receptors
Oncogenes
Pharmaceutical Preparations
Cell Movement
Cell Survival
Apoptosis
Cell Line
Survival
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
Therapeutics
Population

Keywords

  • Gene amplification
  • Molecular marker
  • Oncogene addiction
  • Targeted therapy

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. / Smolen, Gromoslaw A.; Sordella, Raffaella; Muir, Beth; Mohapatra, Gayatry; Barmettler, Anne; Archibald, Heidi; Kim, Woo J.; Okimoto, Ross A.; Bell, Daphne W.; Sgroi, Dennis C.; Christensen, James G.; Settleman, Jeffrey; Haber, Daniel A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 7, 14.02.2006, p. 2316-2321.

Research output: Contribution to journalArticle

Smolen, GA, Sordella, R, Muir, B, Mohapatra, G, Barmettler, A, Archibald, H, Kim, WJ, Okimoto, RA, Bell, DW, Sgroi, DC, Christensen, JG, Settleman, J & Haber, DA 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, vol. 103, no. 7, pp. 2316-2321. https://doi.org/10.1073/pnas.0508776103
Smolen, Gromoslaw A. ; Sordella, Raffaella ; Muir, Beth ; Mohapatra, Gayatry ; Barmettler, Anne ; Archibald, Heidi ; Kim, Woo J. ; Okimoto, Ross A. ; Bell, Daphne W. ; Sgroi, Dennis C. ; Christensen, James G. ; Settleman, Jeffrey ; Haber, Daniel A. / Amplification of MET may identify a subset of cancers with extreme sensitivity to the selective tyrosine kinase inhibitor PHA-665752. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 7. pp. 2316-2321.
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