Format

Send to

Choose Destination
Clin Cancer Res. 2018 Oct 1;24(19):4845-4853. doi: 10.1158/1078-0432.CCR-18-0864. Epub 2018 Jun 25.

Inhibition of BET Bromodomain Proteins with GS-5829 and GS-626510 in Uterine Serous Carcinoma, a Biologically Aggressive Variant of Endometrial Cancer.

Author information

1
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
2
Department of Experimental Oncology, IEO, Milano, Italy.
3
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
5
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
6
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut.
7
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut. alessandro.santin@yale.edu.

Abstract

Purpose: Uterine serous carcinoma (USC) is a rare and aggressive variant of endometrial cancer. Whole-exome sequencing (WES) studies have recently reported c-Myc gene amplification in a large number of USCs, suggesting c-Myc as a potential therapeutic target. We investigated the activity of novel BET bromodomain inhibitors (GS-5829 and GS-626510, Gilead Sciences Inc.) and JQ1 against primary USC cultures and USC xenografts.Experimental Design: We evaluated c-Myc expression by qRT-PCR in a total of 45 USCs including fresh-frozen tumor tissues and primary USC cell lines. We also performed IHC and Western blot experiments in 8 USC tumors. USC cultures were evaluated for sensitivity to GS-5829, GS-626510, and JQ1 in vitro using proliferation, viability, and apoptosis assays. Finally, the in vivo activity of GS-5829, GS-626510, and JQ1 was studied in USC-ARK1 and USC-ARK2 mouse xenografts.Results: Fresh-frozen USC and primary USC cell lines overexpressed c-Myc when compared with normal tissues (P = 0.0009 and 0.0083, respectively). High c-Myc expression was found in 7 of 8 of primary USC cell lines tested by qRT-PCR and 5 of 8 tested by IHC. In vitro experiments demonstrated high sensitivity of USC cell lines to the exposure to GS-5829, GS-626510, and JQ1 with BET inhibitors causing a dose-dependent decrease in the phosphorylated levels of c-Myc and a dose-dependent increase in caspase activation (apoptosis). In comparative in vivo experiments, GS-5829 and/or GS-626510 were found more effective than JQ1 at the concentrations/doses used in decreasing tumor growth in both USC-ARK1 and USC-ARK2 mouse xenograft models.Conclusions: GS-5829 and GS-626510 may represent novel, highly effective therapeutics agents against recurrent/chemotherapy-resistant USC-overexpressing c-Myc. Clinical studies with GS-5829 in patients with USC harboring chemotherapy-resistant disease are warranted. Clin Cancer Res; 24(19); 4845-53. ©2018 AACR.

PMID:
29941483
PMCID:
PMC6168417
[Available on 2019-10-01]
DOI:
10.1158/1078-0432.CCR-18-0864

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center