TY - JOUR
T1 - Inhibition of BET bromodomain proteins with GS-5829 and GS-626510 in uterine serous carcinoma, a biologically aggressive variant of endometrial cancer
AU - Bonazzoli, Elena
AU - Predolini, Federica
AU - Cocco, Emiliano
AU - Bellone, Stefania
AU - Altwerger, Gary
AU - Menderes, Gulden
AU - Zammataro, Luca
AU - Bianchi, Anna
AU - Pettinella, Francesca
AU - Riccio, Francesco
AU - Han, Chanhee
AU - Yadav, Ghanshyam
AU - Lopez, Salvatore
AU - Manzano, Aranzazu
AU - Manara, Paola
AU - Buza, Natalia
AU - Hui, Pei
AU - Wong, Serena
AU - Litkouhi, Babak
AU - Ratner, Elena
AU - Silasi, Dan Arin
AU - Huang, Gloria S.
AU - Azodi, Masoud
AU - Schwartz, Peter E.
AU - Schlessinger, Joseph
AU - Santin, Alessandro D.
N1 - Funding Information:
This work was supported in part by grants from NIH U01 CA176067-01A1, the Deborah Bunn Alley Foundation, the Tina Brozman Foundation, the Discovery to Cure Foundation and the Guido Berlucchi Foundation to A.D. Santin, and Gilead Sciences Inc. This investigation was also supported by NIH Research Grant CA-16359 from NCI and Stand-Up-To-Cancer (SU2C) convergence 2.0 grant to A.D. Santin.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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 ¼ 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.
AB - 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 ¼ 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.
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U2 - 10.1158/1078-0432.CCR-18-0864
DO - 10.1158/1078-0432.CCR-18-0864
M3 - Article
C2 - 29941483
AN - SCOPUS:85054057449
SN - 1078-0432
VL - 24
SP - 4845
EP - 4853
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -