Derangements in HUWE1/c-MYC pathway confer sensitivity to the BET bromodomain inhibitor GS-626510 in uterine cervical carcinoma
| Autor: | Joan Tymon-Rosario, Gloria S. Huang, Burak Zeybek, Adele Guglielmi, Stefania Bellone, Peter E. Schwartz, Paola Manara, Elena Bonazzoli, Barbara Gnutti, Nupur Nagarkatti, Vaagn Andikyan, Elena Ratner, Alessandro D. Santin, Gary Altwerger, Silvia Pelligra, Dan-Arin Silasi, Luca Zammataro, Chanhee Han, Masoud Azodi, Gulden Menderes |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
0301 basic medicine Ubiquitin-Protein Ligases medicine.medical_treatment Uterine Cervical Neoplasms Article Proto-Oncogene Proteins c-myc Loss of heterozygosity BET inhibitor Mice Young Adult 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor Cervical carcinoma Animals Humans Medicine Gene silencing In Situ Hybridization Fluorescence Aged Chemotherapy business.industry Tumor Suppressor Proteins Imidazoles Proteins Obstetrics and Gynecology Isoxazoles Middle Aged Xenograft Model Antitumor Assays Bromodomain 030104 developmental biology Real-time polymerase chain reaction Oncology 030220 oncology & carcinogenesis Cancer research Female business Signal Transduction |
| Zdroj: | Gynecol Oncol |
| ISSN: | 0090-8258 |
| Popis: | Objective Whole-exome-sequencing (WES) studies reported c-MYC gene-amplification and HUWE1 gene deletion/mutations in a significant number of cervical-cancer-patients (CC) suggesting HUWE1/c-MYC pathway as potential therapeutic target. We investigated HUWE1/c-MYC expression in fresh-frozen-CC and the activity of the novel BET inhibitor GS-626510 (Gilead-Science-Inc) against primary WES CC-cultures and CC-xenografts. Methods HUWE1 and c-MYC expression were evaluated by qRT-PCR in 23 CC including 12 fresh-frozen-tumor-tissues and 11 primary-cell-lines. c-Myc expression was also evaluated by Western-Blot (WB) and fluorescence-in-situ-hybridization (FISH) in all 11 fully sequenced primary-CC-cell-lines. Primary tumors were evaluated for sensitivity to GS-626510 in-vitro using proliferation and viability-assays. siRNA experiments were used to evaluate the effect of HUWE1 silencing on primary-CC-cell-line growth and sensitivity to GS-626510. Finally, the in-vivo activity of GS-626510 was studied in CC-CVX8-mouse-xenografts. Results Fresh-frozen-CC and primary-CC-cell-lines overexpressed c-MYC when compared to normal tissues (p = .01). FISH demonstrated amplification of c-MYC in 9/11 (82%) of the primary-CC-cell-lines. Cell-lines with derangements in HUWE1/c-MYC pathway were highly sensitive to GS-626510, with a dose-response decrease in cell proliferation and viability. siRNA silencing of HUWE1 significantly increased c-MYC expression and CC cell-proliferation and enhanced the in-vitro sensitivity to GS-626510. Twice-daily oral doses of GS-626510 were well tolerated in-vivo and highly effective in decreasing tumor-growth (p = .004) and increasing survival (p = .004) of CC-CVX8 xenografts. Conclusions Downregulation/inactivation of HUWE1 may increase c-MYC expression and proliferation in primary-CC-cell-lines. GS-626510 may represent a novel, potentially highly effective therapeutic agent against CC overexpressing c-MYC and/or harboring HUWE1 mutations. Clinical studies with BET inhibitor in CC-patients harboring radiation/chemotherapy-resistant disease are warranted. |
| Databáze: | OpenAIRE |
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