Selective targeting of cyclin E1-amplified high-grade serous ovarian cancer by cyclin-dependent kinase 2 and AKT Inhibition
Purpose: Cyclin E1 (CCNE1) amplification is associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). Here, we explore approaches to target CCNE1-amplified cancers and potential strategies to overcome resistance to targeted agents.Experimental Design: To examine dependency on CDK2 in CCNE1-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 CCNE1 and the AKT pathway was further explored in genomic data from primary tumors, and functional studies in fallopian tube secretory cells.Results: We validate CDK2 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 CCNE1-amplified HGSC, including dinaciclib and AKT inhibitors. Analysis of genomic data from TCGA demonstrated coamplification of CCNE1 and AKT2 Overexpression of Cyclin E1 and AKT isoforms, in addition to mutant TP53, imparted malignant characteristics in untransformed fallopian tube secretory cells, the dominant site of origin of HGSC.Conclusions: These findings suggest a specific dependency of CCNE1-amplified tumors for AKT activity, and point to a novel combination of dinaciclib and AKT inhibitors that may selectively target patients with CCNE1-amplified HGSC. Clin Cancer Res; 23(7); 1862-74. (c)2016 AACR.
|ISBN||1078-0432 (Print) 1078-0432 (Linking)|
|Authors||Au-Yeung, G.; Lang, F.; Azar, W. J.; Mitchell, C.; Jarman, K. E.; Lackovic, K.; Aziz, D.; Cullinane, C.; Pearson, R. B.; Mileshkin, L.; Rischin, D.; Karst, A. M.; Drapkin, R.; Etemadmoghadam, D.; Bowtell, D. D.|
|Responsible Garvan Author|
|Publisher Name||CLINICAL CANCER RESEARCH|
|Published Date||2017-04-01 00:00:00|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/27663592|