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.
Elena Bonazzoli  1 ,  Federica Predolini  2 ,  Emiliano Cocco  3 ,  Stefania Bellone  1 ,  Gary Altwerger  1 ,  Gulden Menderes  1 ,  Luca Zammataro  1 ,  Anna Bianchi  1 ,  Francesca Pettinella  1 ,  Francesco Riccio  1 ,  Chanhee Han  1 ,  Ghanshyam Yadav  1 ,  Salvatore Lopez  1  4 ,  Aranzazu Manzano  1 ,  Paola Manara  1 ,  Natalia Buza  5 ,  Pei Hui  5 ,  Serena Wong  5 ,  Babak Litkouhi  1 ,  Elena Ratner  1 ,  Dan-Arin Silasi  1 ,  Gloria S Huang  1 ,  Masoud Azodi  1 ,  Peter E Schwartz  1 ,  Joseph Schlessinger  6 ,  Alessandro D Santin  7
Affiliations
  • 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. [email protected].
PMID: 29941483 DOI: 10.1158/1078-0432.CCR-18-0864
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.

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