Cancer Therapy: Preclinical Resistance toCDK2 Inhibitors IsAssociatedwithSelection of Polyploid Cells in CCNE1-Amplified Ovarian Cancer

Purpose: Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, and is themost prominent structural variant associatedwith primary treatment failure in highgrade 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. Experimental Design:We examined the effect of CDK2 suppression using RNA interference and smallmolecule inhibitors in SK-OV-3,OVCAR-4, andOVCAR-3 ovarian cancer cell lines. To identifymechanisms of resistance,wederivedmultiple, independent resistant sublines ofOVCAR-3 toCDK2 inhibitors. Resistant cellswere extensively characterizedby gene expression and copynumber 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. Results: 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. Conclusions: These findings suggest that cyclinE1/CDK2 is an important therapeutic target inHGSC, but that resistance to CDK2 inhibitors may emerge due to upregulation of CDK2 target protein and through preexisting cellular polyploidy. Clin Cancer Res; 19(21); 5960–71. 2013 AACR.