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Bromodomain 4 inhibition leads to MYCN downregulation in Wilms' tumor cells

By Andrew D. Woods, Noah E Berlow, Reshma Purohit, Katherine E. Tranbarger Freier, Joel E Michalek, Melvin Lathara, Kevin Matlock, Ganapati Srivivasa, Brigitte Royer-Pokora, Renata Veselska, Charles Keller

Posted 04 Jan 2021
bioRxiv DOI: 10.1101/2021.01.04.425208

Wilms tumor is the most common childhood kidney cancer. Two distinct histological subtypes of Wilms tumor have been described: tumors lacking anaplasia (the favorable subtype) and tumors displaying anaplastic features (the unfavorable subtype). Children with favorable disease generally have a very good prognosis, while those with anaplasia are oftentimes refractory to standard treatments and suffer poor outcomes. MYCN dysregulation has been associated with a number of pediatric cancers including the anaplastic subtype of Wilms tumor. In this context, we undertook a functional genomics approach to uncover novel therapeutic strategies for those patients with anaplastic Wilms tumor. Genomic analysis and in vitro experimentation demonstrate that Wilms tumor cell growth can be reduced by modulating MYCN overexpression via BRD4 inhibition. We observed a time dependent reduction of MYCN and MYC protein levels upon BRD4 inhibition in Wilms tumor cell lines which led to increased cell death and suppressed proliferation. We suggest that AZD5153, a novel dual-BRD4 inhibitor, can reduce MYCN levels and should be further explored for its therapeutic potential against Wilms tumor.

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