Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo

Emiliano Cocco, 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.
Salvatore Lopez, Division of Gynecologic Oncology, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy.
Jonathan Black, 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.
Stefania Bellone, 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.
Elena Bonazzoli, 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.
Federica Predolini, 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.
Francesca Ferrari, 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.
Carlton L. Schwab, 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.
Gulden Menderes, 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.
Luca Zammataro, 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.
Natalia Buza, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Pei Hui, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Serena Wong, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Siming Zhao, Department of Genetics, Yale University, New Haven, CT 06520, USA.
Yalai Bai, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
David L. Rimm, Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
Elena Ratner, 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.
Babak Litkouhi, 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.
Dan-Arin Silasi, 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.
Masoud Azodi, 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.
Peter E. Schwartz, 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.
Alessandro D. Santin, 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.

Document Type

Article

Publication Title

British journal of cancer

Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Dual CCNE1/PIK3CA blockade may represent a novel therapeutic option for USC patients harbouring recurrent CCNE1-amplified/pi3kca-mutated tumours.

First Page

303

Last Page

11

DOI

10.1038/bjc.2016.198

Publication Date

7-26-2016

Identifier

27351214 (pubmed); PMC4973158 (pmc); 10.1038/bjc.2016.198 (doi); bjc2016198 (pii)

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