Journal article
Selective targeting of Cyclin E1-amplified high-grade serous ovarian cancer by Cyclin-dependent kinase 2 and AKT inhibition
G Au-Yeung, F Lang, WJ Azar, C Mitchell, KE Jarman, K Lackovic, D Aziz, C Cullinane, RB Pearson, L Mileshkin, D Rischin, AM Karst, R Drapkin, D Etemadmoghadam, DDL Bowtell
Clinical Cancer Research | AMER ASSOC CANCER RESEARCH | Published : 2017
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. 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 path..
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Grants
Awarded by National Cancer Institute
Funding Acknowledgements
This work was supported by a National Health and Medical Research Council (NHMRC) program grant (APP1092856; to D. D. L. Bowtell), NHMRC project grant (APP1042358; to D. Etemadmoghadam), a Pfizer Cancer Research Grant (WI80176; to G. Au-Yeung), University of Melbourne Australian Postgraduate Award (to G. Au-Yeung), the U. S. Army Medical Research and Materiel Command (OC140511; to D. D. L. Bowtell and R. Drapkin), the National Cancer Institute at the NIH (P50-CA083636 and R21 CA156021; to R. Drapkin); the Honorable Tina Brozman 'Tina's Wish' Foundation (to R. Drapkin), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to R. Drapkin), a Canadian Institutes of Health Research Fellowship (to A. M. Karst), a Kaleidoscope of Hope Foundation Young Investigator Research grant (to A. M. Karst), the Basser Center for BRCA, and Department of Obstetrics and Gynecology at the University of Pennsylvania Perelman School of Medicine (to R. Drapkin). The Australian Ovarian Cancer Study is supported by the Peter MacCallum Cancer Centre Foundation, U. S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Foundation of Western Australia, The Cancer Council Tasmania, and the National Health and Medical Research Council of Australia (NHMRC; ID# 628779), Stephanie Boldeman, the Agar family, and Ovarian Cancer Australia.