Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells in CCNE1-Amplified Ovarian Cancer

• Published in: Clinical cancer research 2013-11, Vol.19 (21), p.5960-5971
• Main Authors: ETEMADMOGHADAM, Dariush, AU-YEUNG, George, CARTER, Scott, GRESSHOFF, Irma, MILESHKIN, Linda, RISCHIN, Danny, HAHN, William C, WARING, Paul M, GETZ, Gad, CULLINANE, Carleen, CAMPBELL, Lynda J, BOWTELL, David D, WALL, Meaghan, MITCHELL, Chris, KANSARA, Maya, LOEHRER, Elizabeth, BATZIOS, Crisoula, GEORGE, Joshy, FTOUNI, Sarah, WEIR, Barbara A
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cell Survival - genetics; Cluster Analysis; Cyclin E - genetics; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - genetics; Cyclin-Dependent Kinase 2 - metabolism; Drug Resistance, Neoplasm - genetics; Female; Female genital diseases; Gene Amplification; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gynecology. Andrology. Obstetrics; Humans; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncogene Proteins - genetics; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Pharmacology. Drug treatments; Polyploidy; Protein Kinase Inhibitors - pharmacology; Pyrazoles - pharmacology; Pyrrolidinones - pharmacology; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-1337

Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, and is the most prominent structural variant associated with primary treatment failure in high-grade serous ovarian cancer (HGSC). We have previously shown that CCNE1-amplified tumors show amplicon-dependent sensitivity to CCNE1 suppression. Here, we explore targeting CDK2 as a novel therapeutic strategy in CCNE1-amplified cancers and mechanisms of resistance. We examined the effect of CDK2 suppression using RNA interference and small-molecule inhibitors in SK-OV-3, OVCAR-4, and OVCAR-3 ovarian cancer cell lines. To identify mechanisms of resistance, we derived multiple, independent resistant sublines of OVCAR-3 to CDK2 inhibitors. Resistant cells were extensively characterized by gene expression and copy number analysis, fluorescence-activated cell sorting profiling and conventional karyotyping. In addition, we explored the relationship between CCNE1 amplification and polyploidy using data from primary tumors. We validate CDK2 as a therapeutic target in CCNE1-amplified cells by showing selective sensitivity to suppression, either by gene knockdown or using small-molecule inhibitors. In addition, we identified two resistance mechanisms, one involving upregulation of CDK2 and another novel mechanism involving selection of polyploid cells from the pretreatment tumor population. Our analysis of genomic data shows that polyploidy is a feature of cancer genomes with CCNE1 amplification. These findings suggest that cyclinE1/CDK2 is an important therapeutic target in HGSC, but that resistance to CDK2 inhibitors may emerge due to upregulation of CDK2 target protein and through preexisting cellular polyploidy.