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Title: Insulin-Like Growth Factor–Type 1 Receptor Inhibitor NVP-AEW541 Enhances Radiosensitivity of PTEN Wild-Type but Not PTEN-Deficient Human Prostate Cancer Cells
Authors: Isebaert, Sofie F ×
Swinnen, Johan
McBride, William H.
Haustermans, Karin #
Issue Date: 1-Sep-2011
Publisher: Pergamon Press
Series Title: International Journal of Radiation Oncology, Biology, Physics vol:81 issue:1 pages:239-247
Abstract: Purpose
During the past decade, many clinical trials with both monoclonal antibodies and small molecules that target the insulin-like growth factor–type 1 receptor (IGF-1R) have been launched. Despite the important role of IGF-1R signaling in radioresistance, studies of such agents in combination with radiotherapy are lagging behind. Therefore, the aim of this study was to investigate the effect of the small molecule IGF-1R kinase inhibitor NVP-AEW541 on the intrinsic radioresistance of prostate cancer cells.

Methods and Materials
The effect of NVP-AEW541 on cell proliferation, cell viability, IGF-1R signaling, radiosensitivity, cell cycle distribution, and double strand break repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the importance of the PTEN pathway status was explored by means of transfection experiments with constitutively active Akt or inactive kinase-dead Akt.

Results
NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. Radiosensitization was observed in the PTEN wild-type cell lines DU145 and 22Rv1 but not in the PTEN-deficient PC3 cell line. NVP-AEW541–induced radiosensitization coincided with downregulation of phospho-Akt levels and high levels of residual double strand breaks. The importance of PTEN status in the radiosensitization effect was confirmed by transfection experiments with constitutively active Akt or inactive kinase-dead Akt.

Conclusions
NVP-AEW541 enhances the effect of ionizing radiation in PTEN wild-type, but not in PTEN-deficient, prostate cancer cells. Proper patient selection based on the PTEN status of the tumor will be critical to the achievement of optimal results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored.
ISSN: 0360-3016
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Lipid Metabolism and Cancer (+)
Laboratory of Experimental Radiotherapy
× corresponding author
# (joint) last author

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