title: Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo.
abstract: Clinical options for patients harbouring advanced/recurrent uterine serous carcinoma (USC), an aggressive variant of endometrial tumour, are very limited. Next-generation sequencing (NGS) data recently demonstrated that cyclin E1 (CCNE1) gene amplification and pik3ca driver mutations are common in USC and may therefore represent ideal therapeutic targets.
  
  
  
  Cyclin E1 expression was evaluated by immunohistochemistry (IHC) on 95 USCs. The efficacy of the cyclin-dependent kinase 2/9 inhibitor CYC065 was assessed on multiple primary USC cell lines with or without CCNE1 amplification. Cell-cycle analyses and knockdown experiments were performed to assess CYC065 targeting specificity. Finally, the in vitro and in vivo activity of CYC065, Taselisib (a PIK3CA inhibitor) and their combinations was tested on USC xenografts derived from CCNE1-amplified/pik3ca-mutated USCs.
  
  
  
  We found that 89.5% of the USCs expressed CCNE1. CYC065 blocked cells in the G1 phase of the cell cycle and inhibited cell growth specifically in CCNE1-overexpressing USCs. Cyclin E1 knockdown conferred increased resistance to CYC065, whereas CYC065 treatment of xenografts derived from CCNE1-amplified USCs significantly reduced tumour growth. The combination of CYC065 and Taselisib demonstrated synergistic effect in vitro and was significantly more effective than single-agent treatment in decreasing tumour growth in xenografts of CCNE1-amplified/pik3ca-mutated USCs.
  
  
  
  Dual CCNE1/PIK3CA blockade may represent a novel therapeutic option for USC patients harbouring recurrent CCNE1-amplified/pi3kca-mutated tumours.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Cocco
authors.affiliation: Division of Gynecologic Oncology, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lopez
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Black
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonazzoli
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Predolini
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrari
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Carlton L
authors.initials: CL
authors.lastname: Schwab
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Gulden
authors.initials: G
authors.lastname: Menderes
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Zammataro
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Buza
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Hui
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Serena
authors.initials: S
authors.lastname: Wong
authors.affiliation: Department of Genetics, Yale University, New Haven, CT 06520, USA.
authors.forename: Siming
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yalai
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ratner
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Litkouhi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Dan-Arin
authors.initials: DA
authors.lastname: Silasi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Masoud
authors.initials: M
authors.lastname: Azodi
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Room 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019927:Cyclin E / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D051379:Mice; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D046888:Tissue Array Analysis; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human