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

George Au-Yeung, Franziska Winder, Geb. Lang, Walid J Azar, Chris Mitchell, Kate E Jarman, Kurt Lackovic, Diar Aziz, Carleen Cullinane, Richard B Pearson, Linda Mileshkin, Danny Rischin, Alison M Karst, Ronny Drapkin, Dariush Etemadmoghadam & David D L Bowtell

abstract Cyclin E1 () amplification is associated with primary treatment resistance and poor outcome in high-grade serous ovarian cancer (HGSC). Here, we explore approaches to target -amplified cancers and potential strategies to overcome resistance to targeted agents. To examine dependency on in -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 and the AKT pathway was further explored in genomic data from primary tumors, and functional studies in fallopian tube secretory cells. We validate 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 -amplified HGSC, including dinaciclib and AKT inhibitors. Analysis of genomic data from TCGA demonstrated coamplification of and Overexpression of Cyclin E1 and AKT isoforms, in addition to mutant , imparted malignant characteristics in untransformed fallopian tube secretory cells, the dominant site of origin of HGSC. These findings suggest a specific dependency of -amplified tumors for AKT activity, and point to a novel combination of dinaciclib and AKT inhibitors that may selectively target patients with -amplified HGSC. .
   
citation Au-Yeung G, Winder, Geb. 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 L. Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition. Clin Cancer Res 2017; 23:1862-1874.
   
type journal paper/review (English)
date of publishing 23-9-2017
journal title Clin Cancer Res (23/7)
ISSN print 1078-0432
pages 1862-1874
PubMed 27663592
DOI 10.1158/1078-0432.CCR-16-0620
contact Franziska Winder, geb. Lang