Abstract 836: Insulin-like growth factor-I receptor (IGF-IR) dowregulation in cisplatin-resistant human ovarian cancer cells

Introduction: Ovarian cancer is the most lethal of the gynecological malignancies and the 5th leading cause of cancer related deaths amongst women in the US. It is a chemotherapy-sensitive disease, and about 85% of patients respond to first line treatment with platinum-based chemotherapeutic agents. However, 15% of all patients present with primary platinum-resistant disease, and those with recurrent ovarian cancer develop resistance. Resistance to platinum-based drugs is a major obstacle in ovarian cancer treatment, and mechanisms of platinum resistance are not well understood. Insulin-like growth factor-1 receptor (IGF-1R) signaling has not only been implicated in ovarian cancer development, but has also been suggested to mediate platinum-resistance. The IGF-1R has been proposed as a potential molecular target for ovarian cancer, and clinical trials evaluating the use of small molecule kinase inhibitors or humanized monoclonal antibodies against the IGF-1R are currently under way. This study examines the role of IGF-1R in cisplatin resistance in human ovarian carcinoma. Experimental Procedures: Differential gene expression in two pairs of cisplatin-resistant cell lines (SKOV3-CisR and OVCAR-CisR) and their syngeneic cisplatin-sensitive counterpart (SKOV3 and OVCAR5, respectively) was analyzed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array. IGF-1R mRNA transcripts and protein levels were verified via qRT-PCR and immunoblotting, respectively. Protein expression levels of IGF-1Rα and IGF-1Rα (immunoblotting) were correlated with cisplatin IC50 (XTT cell viability) in a panel of 12 ovarian cancer cell lines. IGF-1R was overexpressed (stable transfection) in SKOV3-CisR cells and the effect on cisplatin sensitivity evaluated. The effect of short-term cisplatin treatment on IGF-1Rα and IGF-1Rα protein levels was studied in SKOV3 and OVCAR5 cells. Results: Cisplatin-resistant SKOV3-CisR and OVCAR5-CisR cells exhibited 2-3 fold lower levels of IGF-1R mRNA transcripts compared to cisplatin-sensitive SKOV3 and OVCAR5 cells in the DNA microarray and via qRT-PCR. Correspondingly, decreased levels of IGF-1Rα and IGF-1Rα protein were found in immunoblot analyses. IGF-1Rα (r = −0.6118; p = 0.0345) and IGF-1Rα (r = −0.5839; p = 0.0462) protein levels and cisplatin IC50were negatively correlated. IGF-1R overexpression in SKOV3-CisR cells sensitized the cells to cisplatin, from 5 μg/ml (SKOV3-CisR) to 10-12 μg/ml (SKOV3-CisR-IGF-1R). Cisplatin induced a decrease in IGF-1Rα and IGF-1Rα levels after 24 and 48 hours treatment. Conclusions: Cisplatin treatment of ovarian cancer cells results in IGF-1R downregulation, which in turn decreases cisplatin sensitivity. Our results have important implications in the design of IGF-1R targeting strategies in clinical trials for ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 836. doi:1538-7445.AM2012-836