Faculty Collaboration Database

Higher levels of c-Met expression and phosphorylation identify cell lines with increased sensitivity to AMG-458, a novel selective c-Met inhibitor with radiosensitizing effects. Int J Radiat Oncol Biol Phys 2012 Nov 15;84(4):e525-31

Date

07/28/2012

Pubmed ID

22836051

DOI

10.1016/j.ijrobp.2012.06.025

Scopus ID

2-s2.0-84872045438 (requires institutional sign-in at Scopus site)   21 Citations

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: 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays assessed the sensitivities of the cells to AMG-458. Clonogenic survival assays illustrated the radiosensitizing effects of AMG-458. Western blot for cleaved caspase 3 measured apoptosis. Immunoblotting for c-Met, phospho-Met (p-Met), Akt/p-Akt, and Erk/p-Erk was performed to observe downstream signaling.

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.

Author List

Li B, Torossian A, Sun Y, Du R, Dicker AP, Lu B

MESH terms used to index this publication - Major topics in bold

Aminopyridines
Apoptosis
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Cell Survival
Drug Screening Assays, Antitumor
Humans
Lung Neoplasms
Neoplasm Proteins
Phosphorylation
Proto-Oncogene Proteins c-met
Pyrazoles
Radiation Tolerance
Radiation-Sensitizing Agents