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Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo.
- Source :
-
British journal of cancer [Br J Cancer] 2016 Jul 26; Vol. 115 (3), pp. 303-11. Date of Electronic Publication: 2016 Jun 28. - Publication Year :
- 2016
-
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.<br />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.<br />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.<br />Conclusions: Dual CCNE1/PIK3CA blockade may represent a novel therapeutic option for USC patients harbouring recurrent CCNE1-amplified/pi3kca-mutated tumours.
- Subjects :
- Animals
Antineoplastic Agents therapeutic use
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
Cyclin E metabolism
DNA Copy Number Variations
Female
Gene Knockdown Techniques
Heterografts
Humans
In Situ Hybridization, Fluorescence
In Vitro Techniques
Mice
RNA, Messenger genetics
Tissue Array Analysis
Uterine Neoplasms genetics
Uterine Neoplasms metabolism
Cyclin E genetics
Mutation
Oncogene Proteins genetics
Phosphatidylinositol 3-Kinases genetics
Uterine Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1532-1827
- Volume :
- 115
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- British journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 27351214
- Full Text :
- https://doi.org/10.1038/bjc.2016.198