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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Aurora Kinase A / genetics
  • Aurora Kinase B / genetics
  • Azepines / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cystadenocarcinoma, Serous / drug therapy*
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / pathology
  • Dose-Response Relationship, Drug
  • Endometrial Neoplasms / drug therapy*
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / pathology
  • Exome Sequencing
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Middle Aged
  • Phosphorylation / drug effects
  • Primary Cell Culture
  • Proteins / antagonists & inhibitors
  • Proteins / genetics*
  • Proto-Oncogene Proteins c-myc / genetics
  • Triazoles / pharmacology
  • Uterine Neoplasms / drug therapy*
  • Uterine Neoplasms / genetics
  • Uterine Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • (+)-JQ1 compound
  • Antineoplastic Agents
  • Azepines
  • MYC protein, human
  • Proteins
  • Proto-Oncogene Proteins c-myc
  • Triazoles
  • bromodomain and extra-terminal domain protein, human
  • AURKA protein, human
  • AURKB protein, human
  • Aurora Kinase A
  • Aurora Kinase B