Abstract | PURPOSE: c-Met is overexpressed in some non-small cell lung cancer (NSCLC) cell lines and tissues. Cell lines with higher levels of c-Met expression and phosphorylation depend on this receptor for survival. We studied the effects of AMG-458 on 2 NSCLC cell lines. METHODS AND MATERIALS: RESULTS:
AMG-458 enhanced radiosensitivity in H441 but not in A549. H441 showed constitutive phosphorylation of c-Met. A549 expressed low levels of c-Met, which were phosphorylated only in the presence of exogenous hepatocyte growth factor. The combination of radiation therapy and AMG-458 treatment was found to synergistically increase apoptosis in the H441 cell line but not in A549. Radiation therapy, AMG-458, and combination treatment were found to reduce p-Akt and p-Erk levels in H441 but not in A549. H441 became less sensitive to AMG-458 after small interfering RNA knockdown of c-Met; there was no change in A549. After overexpression of c-Met, A549 became more sensitive, while H441 became less sensitive to AMG-458. CONCLUSIONS:
AMG-458 was more effective in cells that expressed higher levels of c-Met/p-Met, suggesting that higher levels of c-Met and p-Met in NSCLC tissue may classify a subset of tumors that are more sensitive to molecular therapies against this receptor.
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Authors | Bo Li, Artour Torossian, Yunguang Sun, Ruihong Du, Adam P Dicker, Bo Lu |
Journal | International journal of radiation oncology, biology, physics
(Int J Radiat Oncol Biol Phys)
Vol. 84
Issue 4
Pg. e525-31
(Nov 15 2012)
ISSN: 1879-355X [Electronic] United States |
PMID | 22836051
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2012 Elsevier Inc. All rights reserved. |
Chemical References |
- 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
- Aminopyridines
- Neoplasm Proteins
- Pyrazoles
- Radiation-Sensitizing Agents
- Proto-Oncogene Proteins c-met
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Topics |
- Aminopyridines
(pharmacology)
- Apoptosis
(drug effects, radiation effects)
- Carcinoma, Non-Small-Cell Lung
(drug therapy, metabolism, pathology, radiotherapy)
- Cell Line, Tumor
(drug effects, radiation effects)
- Cell Survival
- Drug Screening Assays, Antitumor
(methods)
- Humans
- Lung Neoplasms
(drug therapy, metabolism, pathology, radiotherapy)
- Neoplasm Proteins
(antagonists & inhibitors, metabolism)
- Phosphorylation
- Proto-Oncogene Proteins c-met
(antagonists & inhibitors, metabolism)
- Pyrazoles
(pharmacology)
- Radiation Tolerance
(drug effects)
- Radiation-Sensitizing Agents
(pharmacology)
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