Hyperactivation of the Insulin-like Growth Factor Receptor I Signaling Pathway Is an Essential Event for Cisplatin Resistance of Ovarian Cancer Cells

¹Center of Advanced European Studies and Research (caesar), Bonn, Germany; ²Institute of Human Genetics and Anthropology and ³Pharmaceutical Biochemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine University of Düsseldorf, Düsseldorf, Germany; and ⁴Institute of Pathology, Charité University Hospital, Berlin, Germany

^* To whom correspondence should be addressed. E-mail: royer{at}caesar.de.

	Abstract

Platinum plays a central role in the therapy of ovarian cancer, and the emergence of platinum resistance is a major obstacle for clinical management of the disease. We treated A2780 ovarian cancer cells by weekly cycles of cisplatin over a period of 6 months and unveiled that enhanced insulin-like growth factor I receptor (IGF-IR) expression and autocrine IGF-I are associated with hyperactivation of the IGF-IR and phosphatidylinositol-3-OH kinase (PI3K) pathways in cisplatin-resistant cells. IGF-IR expression levels increased during treatment cycles and correlated with cisplatin resistance. Purified IGF-I induced cisplatin resistance in diverse ovarian cancer cell lines, and small molecule inhibitors proved that IGF-IR and PI3K are essential for cisplatin resistance. Similar results were obtained with BG-1 ovarian cancer cells. Cytogenetic and array comparative genomic hybridization analyses revealed selection and de novo formation of chromosomal alterations during resistance development. An analysis of gene expression profiles of primary ovarian carcinomas identified the regulatory subunit PIK3R2 of PI3-kinase as a significant negative prognosis factor for ovarian cancer. We conclude that targeting the IGF-IR and the PI3K pathways is a promising new strategy to treat cisplatin-resistant ovarian carcinomas. [Cancer Res 2009;69(7):2996–3003]

Key Words: ovarian cancer, cisplatin resistance, IGF-IR pathway, autocrine IGF-I, PI3K pathway