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Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometroid and serous papillary endometrial cancer cell lines

Attias-Geva, Zohar and Bentov, Itay and Fishman, Ami and Werner, Haim and Bruchim, Ilan and Jeay, Sebastien (2011) Insulin-like growth factor-I receptor inhibition by specific tyrosine kinase inhibitor NVP-AEW541 in endometroid and serous papillary endometrial cancer cell lines. Gynecologic Oncology. ISSN 0090-8258

Abstract

Endometrial cancer is the most widespread gynecological cancer in Western countries and constitutes a major public health issue. The role of the insulin-like growth factor (IGF) system in endometrial biology as well as in endometrial cancer has been well established. The IGF-I receptor (IGF-IR) emerged in recent years as a promising therapeutic target in a number of cancers. NVP-AEW541 (Novartis Pharma) is a pyrrolo(2,3-d)pyrimidine derivative with specific IGF-IR tyrosine kinase inhibitory activity. NVP-AEW541 has been shown to specifically abrogate IGF-I-mediated IGF-IR autophosphorylation and to reduce activation of the IGF-IR downstream signaling pathways. The aim of the present study was to investigate the potential anti-proliferative activities of NVP-AEW541 in Type I (endometrioid) and Type II (uterine serous papillary endometrial carcinoma, USPC) endometrial cancer cell lines. Results obtained showed that NVP-AEW541 abolished the IGF-I stimulated IGF-IR phosphorylation in all of the cell lines investigated (ECC-1, Ishikawa, USPC-1, USPC-2), whereas it abolished AKT and ERK phosphorylation in ECC-1 and USPC-1 cells. Furthermore, the inhibitor prevented from IGF-I from exerting its antiapoptotic effect in ECC-1, USPC-1 and USPC-2 cells. In addition, proliferation assays showed that NVP-AEW541 caused a significant decrease in proliferation rate in all of the cell lines. NVP-AEW541 had no major effect on the insulin receptor. In summary, our results suggest that specific IGF-IR inhibition by NVP-AEW541 is a promising therapeutic tool in endometrial cancer.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/3053

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