Abstract | BACKGROUND: No comprehensive data are available on the molecular predictors of sensitivity to MET inhibitor in lung carcinomas. METHODS: RESULTS: Of the 41 cells, 8 were highly or intermediately sensitive to PHA665752, and the remainder were PHA665752 resistant. The sensitive cells (n = 8) included not only 4 of 4 MET-amplified cell lines but also 2 of 11 KRAS-mutated cell lines and 1 of 6 EGFR-mutated cell lines. Unlike the MET-amplified cell lines, both the MET-mutated cell lines were PHA665752 resistant. High phospho-MET was not restricted to the four MET-amplified cell lines. To the contrary, it was also found in 9 of 37 MET-nonamplified cell lines, including 3 of 6 EGFR-mutated cell lines and 4 of 11 KRAS-mutated cell lines. High phospho-MET was correlated with PHA665752 sensitivity in the entire panel of cell lines, especially in the KRAS-mutated cells. The AKT and ERK pathways in the high phospho-MET cell lines were dependent on MET activation in MET-amplified and KRAS-mutated cells but not in EGFR-mutated and human epidermal growth factor receptor 2-amplified cells. CONCLUSIONS: MET amplification is an excellent predictor of PHA665752 sensitivity but not the sole predictor. High phospho-MET and dependence of the AKT and ERK pathways on MET activation may predict sensitivity to PHA665752, especially in KRAS-mutated cell lines.
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Authors | Daisuke Matsubara, Shumpei Ishikawa, Sachiko Oguni, Hiroyuki Aburatani, Masashi Fukayama, Toshiro Niki |
Journal | Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
(J Thorac Oncol)
Vol. 5
Issue 9
Pg. 1317-24
(Sep 2010)
ISSN: 1556-1380 [Electronic] United States |
PMID | 20736805
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 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
- Biomarkers, Tumor
- Indoles
- KRAS protein, human
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins
- Receptors, Growth Factor
- Sulfones
- EGFR protein, human
- ErbB Receptors
- MET protein, human
- Proto-Oncogene Proteins c-met
- Proto-Oncogene Proteins p21(ras)
- ras Proteins
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Topics |
- Biomarkers, Tumor
(genetics, metabolism)
- Blotting, Western
- Carcinoma, Non-Small-Cell Lung
(diagnosis, drug therapy, metabolism)
- Cell Proliferation
- Drug Resistance, Neoplasm
(drug effects)
- Epithelial-Mesenchymal Transition
- ErbB Receptors
(genetics, metabolism)
- Gene Amplification
- Gene Expression Profiling
- Humans
- Indoles
(pharmacology)
- Lung Neoplasms
(diagnosis, drug therapy, metabolism)
- Mutation
(genetics)
- Oligonucleotide Array Sequence Analysis
- Phosphorylation
(drug effects)
- Polymerase Chain Reaction
- Polymorphism, Single Nucleotide
(genetics)
- Predictive Value of Tests
- Protein Kinase Inhibitors
(pharmacology)
- Proto-Oncogene Proteins
(genetics, metabolism)
- Proto-Oncogene Proteins c-met
(antagonists & inhibitors, genetics, metabolism)
- Proto-Oncogene Proteins p21(ras)
- Receptors, Growth Factor
(antagonists & inhibitors, genetics, metabolism)
- Signal Transduction
- Sulfones
(pharmacology)
- Tumor Cells, Cultured
- ras Proteins
(genetics, metabolism)
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