Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition

Abstract

<b>Purpose:</b> Cyclin E1 (<i>CCNE1</i>) amplification is associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). Here, we explore approaches to target <i>CCNE1</i>-amplified cancers and potential strategies to overcome resistance to targeted agents.<b>Experimental Design:</b> To examine dependency on <i>CDK2</i> in <i>CCNE1</i>-amplified HGSC, we utilized siRNA and conditional shRNA gene suppression, and chemical inhibition using dinaciclib, a small-molecule CDK2 inhibitor. High-throughput compound screening was used to identify selective synergistic drug combinations, as well as combinations that may overcome drug resistance. An observed relationship between <i>CCNE1</i> and the AKT pathway was further explored in genomic data from primary tumors, and functional studies in fallopian tube secretory cells.<b>Results:</b> We validate <i>CDK2</i> as a therapeutic target by demonstrating selective sensitivity to gene suppression. However, we found that dinaciclib did not trigger amplicon-dependent sensitivity in a panel of HGSC cell lines. A high-throughput compound screen identified synergistic combinations in <i>CCNE1</i>-amplified HGSC, including dinaciclib and AKT inhibitors. Analysis of genomic data from TCGA demonstrated coamplification of <i>CCNE1</i> and <i>AKT2</i> Overexpression of Cyclin E1 and AKT isoforms, in addition to mutant <i>TP53</i>, imparted malignant characteristics in untransformed fallopian tube secretory cells, the dominant site of origin of HGSC.<b>Conclusions:</b> These findings suggest a specific dependency of <i>CCNE1</i>-amplified tumors for AKT activity, and point to a novel combination of dinaciclib and AKT inhibitors that may selectively target patients with <i>CCNE1</i>-amplified HGSC. <i>Clin Cancer Res; 23(7); 1862-74. ©2016 AACR</i>.