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

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 cisplatinresistant 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 cisplatinresistant ovarian carcinomas.

A Novel Small-Molecule Aurora Kinase Inhibitor Attenuates Breast Tumor–Initiating Cells and Overcomes Drug Resistance

“…Chemoresistance can be a consequence of cell intrinsic genetic changes, such as reprogramming of metabolic pathways, upregulation of drug efflux pumps, activation of detoxifying enzymes, or apoptotic defects (2,3). In addition, chemoresistance can also result from cell extrinsic factors, such as cytokines and growth factors (4,5). The intrinsic or extrinsic mechanisms of chemoresistance have been demonstrated to be a major cause of cancer treatment failure.…”

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

“…Moreover, a separate line of indirect evidence for the relevance of IGF signaling for neoplasia comes from the observation that there is considerable interindividual variation in circulating IGF-I levels, and that risk and prognosis of certain cancers are related to circulating IGF-I concentration (2,14,15). Finally, IGF signaling may also play a role as a resistance mechanism, which limits the effectiveness of cytotoxic or targeted anticancer agents, including rapalogs (16)(17)(18)(19)(20)(21).…”

Candidate DNA methylation drivers of acquired cisplatin resistance in ovarian cancer identified by methylome and expression profiling

“…Several mechanisms have been suggested to participate in conferring platinum-resistant properties to a tumour cell such as genetic alterations in genes involved in DNA repair, drug uptake, apoptosis, cell cycle control and IGF signalling pathways (Johnstone et al, 2002;Luqmani, 2005;Edwards et al, 2008;Broxterman et al, 2009;Eckstein et al, 2009). More recently, it has been proposed that, in addition to genetic changes, aberrant epigenetic marks can critically contribute to the acquisition of drug resistance (Sharma et al, 2010).…”