C-Met inhibitor MK-8003 radiosensitizes c-Met-expressing non-small-cell lung cancer cells with radiation-induced c-Met-expression.

Abstract

INTRODUCTION:

The radiation doses used to treat unresectable lung cancer are often limited by the proximity of normal tissues. Overexpression of c-Met, a receptor tyrosine kinase, occurs in about half of non-small-cell lung cancers (NSCLCs) and has been associated with resistance to radiation therapy and poor patient survival. We hypothesized that inhibiting c-Met would increase the sensitivity of NSCLC cells to radiation, enhancing the therapeutic ratio, which may potentially translate into improved local control.

METHODS:

We tested the radiosensitivity of two high-c-Met-expressing NSCLC lines, EBC-1 and H1993, and two low-c-Met-expressing lines, A549 and H460, with and without the small-molecule c-Met inhibitor MK-8033. Proliferation and protein expression were measured with clonogenic survival assays and Western blotting, respectively. γ-H2AX levels were evaluated by immunofluorescence staining.

RESULTS:

MK-8033 radiosensitized the high-c-Met-expressing EBC-1 and H1993 cells but not the low-c-Met-expressing cell lines A549 and H460. However, irradiation of A549 and H460 cells increased the expression of c-Met protein at 30 minutes after the irradiation. Subsequent targeting of this up-regulated c-Met by using MK-8033 followed by a second radiation dose reduced the clonogenic survival of both A549 and H460 cells. MK-8033 reduced the levels of radiation-induced phosphorylated (activated) c-Met in A549 cells.

CONCLUSIONS:

These results suggest that inhibition of c-Met could be an effective strategy to radiosensitize NSCLC tumors with high basal c-Met expression or tumors that acquired resistance to radiation because of up-regulation of c-Met.

• Authors: Vikas Bhardwaj, Yanai Zhan, Maria Angelica Cortez, Kie Kian Ang, David Molkentine, Anupama Munshi, Uma Raju, Ritsuko Komaki, John V Heymach, James Welsh
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 7 Issue 8 Pg. 1211-7 (Aug 2012) ISSN: 1556-1380 [Electronic] United States
• PMID: 22617250 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cesium Radioisotopes
• Radiation-Sensitizing Agents
• Proto-Oncogene Proteins c-met

Topics

• Apoptosis (drug effects, radiation effects)
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (metabolism, pathology, radiotherapy)
• Cell Line, Tumor
• Cesium Radioisotopes
• Fluorescent Antibody Technique
• Humans
• Lung Neoplasms (metabolism, pathology, radiotherapy)
• Phosphorylation (drug effects, radiation effects)
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (therapeutic use)
• Tumor Stem Cell Assay