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 targetCCNE1-amplified cancers and potential strategies to overcome resistance to targeted agents.Experimental Design:To examine dependency onCDK2inCCNE1-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 betweenCCNE1and the AKT pathway was further explored in genomic data from primary tumors, and functional studies in fallopian tube secretory cells.Results:We validateCDK2as 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 inCCNE1-amplified HGSC, including dinaciclib and AKT inhibitors. Analysis of genomic data from TCGA demonstrated coamplification ofCCNE1andAKT2Overexpression of Cyclin E1 and AKT isoforms, in addition to mutantTP53, imparted malignant characteristics in untransformed fallopian tube secretory cells, the dominant site of origin of HGSC.Conclusions:These findings suggest a specific dependency ofCCNE1-amplified tumors for AKT activity, and point to a novel combination of dinaciclib and AKT inhibitors that may selectively target patients withCCNE1-amplified HGSC.Clin Cancer Res; 23(7); 1862-74. ©2016 AACR.
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, Victoria, Australia.
George
G
Au-Yeung
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Franziska
F
Lang
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Walid J
WJ
Azar
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Chris
C
Mitchell
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Kate E
KE
Jarman
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
Kurt
K
Lackovic
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
Diar
D
Aziz
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Translational Research Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Carleen
C
Cullinane
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
Richard B
RB
Pearson
Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Linda
L
Mileshkin
Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Danny
D
Rischin
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
Alison M
AM
Karst
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Penn Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Ronny
R
Drapkin
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
Dariush
D
Etemadmoghadam
Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. david.bowtell@petermac.org.|Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Parkville, Victoria, Australia.|Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.|Kinghorn Cancer Centre, Garvan Institute for Medical Research, Darlinghurst, New South Wales, Australia.
David D L
DD
Bowtell
D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides; D019927:Cyclin E / Q000235:genetics*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007212:Indolizines; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011726:Pyridinium Compounds / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics
D019086:Bridged Bicyclo Compounds, Heterocyclic; C475820:CCNE1 protein, human; D003497:Cyclic N-Oxides; D019927:Cyclin E; D007212:Indolizines; D015513:Oncogene Proteins; D011726:Pyridinium Compounds; D034741:RNA, Small Interfering; C553669:dinaciclib; D051058:Oncogene Protein v-akt; D051357:Cyclin-Dependent Kinase 2
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