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Insulin-like growth factor – type 1 receptor inhibitor NVP-AEW541 enhances radiosensitivity of PTEN wild-type but not PTEN-deficient human prostate cancer cells

Isebaert, Sofie / F and Swinnen, Johan / V and McBride, William / H and Haustermans, Karin / M (2011) Insulin-like growth factor – type 1 receptor inhibitor NVP-AEW541 enhances radiosensitivity of PTEN wild-type but not PTEN-deficient human prostate cancer cells. Int. J. Radiation Oncology Biol. Phys., 81 (1). pp. 239-247. ISSN 0360-3016

Abstract

Purpose: During the last 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, combination studies of such agents 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 (DSB) repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the role of the PTEN status was explored by means of transfection experiments with constitutively active Akt or inactive kinase death Akt.
Results: NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. In contrast to the PTEN-deficient PC3 cell line, radiosensitization was only observed in the PTEN wild-type cell lines DU145 and 22Rv1. NVP-AEW541-induced radiosensitization coincided with downregulation of phospho-Akt levels as well as with high levels of residual DSB. The importance of the PTEN status in the radiosensitization effect was further confirmed by the 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 in order to achieve beneficial results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: IGF-1R – radiosensitization – prostate cancer – PTEN – in vitro
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4265

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