Selective targeting of Cyclin E1 amplified high grade serous ovarian cancer by cyclin-dependent kinase 2 and AKT inhibition

Au-Yeung, G; Lang, F; Azar, WJ; Mitchell, C; Jarman, KE; Lackovic, K; Aziz, D; Cullinane, C; Pearson, RB; Mileshkin, L; Rischin, D; Karst, AM; Drapkin, R; Etemadmoghadam, D; Bowtell, DD

Author(s): Au-Yeung, G; Lang, F; Azar, WJ; Mitchell, C; Jarman, KE; Lackovic, K; Aziz, D; Cullinane, C; Pearson, RB; Mileshkin, L; Rischin, D; Karst, AM; Drapkin, R; Etemadmoghadam, D; Bowtell, DD;
Details: Publication Year 2016-09-23,Volume 23,Issue #7,Page 1862-1874
Journal Title: Clinical Cancer Research
Publication Type: Journal Article
Abstract: 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. EXPERIMENT DESIGN: To examine dependency on CDK2 in CCNE1 amplified HGSC, we utilised 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 co-amplification of CCNE1 and AKT2. Over-expression 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.
Publisher: AACR
Research Division(s): Chemical Biology
PubMed ID: 27663592
Publisher's Version: https://doi.org/10.1158/1078-0432.CCR-16-0620
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2016-10-04 09:29:22

Last Modified: 2020-04-07 02:20:49