A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma

Belamy B Cheung, Ane Kleynhans, Rituparna Mittra, Patrick Y. Kim, Jessica K Holien, Zsuzsanna Nagy, Olivia C. Ciampa, Janith A. Seneviratne, Chelsea Mayoh, Mukesh Raipuria, Satyanarayana Gadde, Hassina Massudi, Iris Poh Ling Wong, Owen Tan, Andrew Gong, Aldwin Suryano, Sonya M. Diakiw, Bing Liu, Greg M. Arndt, Tao LiuNaresh Kumar, Olle Sangfelt, Shizhen Zhu, Murray D. Norris, Michelle Haber, Daniel R. Carter, Michael W Parker, Glenn M. Marshall

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Abstract

Histone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, HDAC inhibitors are much more effective in combination with other anti-cancer agents. To identify novel compounds which act synergistically with HDAC inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed a cell-based, high-throughput drug screen of 10,560 small molecule compounds from a drug-like diversity library and identified a small molecule compound (SE486-11) which synergistically enhanced the cytotoxic effects of SAHA. Effects of drug combinations on cell viability, proliferation, apoptosis and colony forming were assessed in a panel of neuroblastoma cell lines. Treatment with SAHA and SE486-11 increased MYCN ubiquitination and degradation, and markedly inhibited tumorigenesis in neuroblastoma xenografts, and, MYCN transgenic zebrafish and mice. The combination reduced ubiquitin-specific protease 5 (USP5) levels and increased unanchored polyubiquitin chains. Overexpression of USP5 rescued neuroblastoma cells from the cytopathic effects of the combination and reduced unanchored polyubiquitin, suggesting USP5 is a therapeutic target of the combination. SAHA and SE486-11 directly bound to USP5 and the drug combination exhibited a 100-fold higher binding to USP5 than individual drugs alone in microscale thermophoresis assays. MYCN bound to the USP5 promoter and induced USP5 gene expression suggesting that USP5 and MYCN expression created a forward positive feedback loop in neuroblastoma cells. Thus, USP5 acts as an oncogenic cofactor with MYCN in neuroblastoma and the novel combination of HDAC inhibitor with SE486-11 represents a novel therapeutic approach for the treatment of MYCN-driven neuroblastoma.

Original languageEnglish
Pages (from-to)2367-2381
Number of pages15
JournalOncogene
Volume40
Issue number13
Early online date3 Mar 2021
DOIs
Publication statusPublished - 1 Apr 2021
Externally publishedYes

Bibliographical note

Copyright © The Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • High-throughput screening
  • Paediatric cancer
  • Target identification

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