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FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma

Oncogene volume 38, pages 6737–6751 (2019)Cite this article

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Abstract

MYCN amplification in neuroblastoma predicts poor prognosis and resistance to therapy. Yet pharmacological strategies of direct MYC inhibition remain unsuccessful due to its “undruggable” protein structure. We herein developed a synthetic lethal screen against MYCN-amplified neuroblastomas using clinically approved therapeutic reagents. We performed a high-throughput screen, from a library of 938 FDA-approved drugs, for candidates that elicit synthetic lethal effects in MYC-driven neuroblastoma cells. The proteasome inhibitors, which are FDA approved for the first-line treatment of multiple myeloma, emerge as top hits to elicit MYC-mediated synthetic lethality. Proteasome inhibition activates the PERK-eIF2α-ATF4 axis in MYC-transformed cells and induces BAX-mediated apoptosis through ATF4-dependent NOXA and TRIB3 induction. A combination screen reveals the proteasome inhibitor bortezomib (BTZ) and the histone deacetylase (HDAC) inhibitor vorinostat (SAHA) concertedly induce dramatic cell death in part through synergistic activation of BAX. This combination causes marked tumor suppression in vivo, supporting dual proteasome/HDAC inhibition as a potential therapeutic approach for MYC-driven cancers. This FDA-approved drug screen with in vivo validation thus provides a rationale for clinical evaluation of bortezomib, alone or in combination with vorinostat, in MYC-driven neuroblastoma patients.

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Acknowledgements

We are grateful to HL and GQ lab members for technical support and critical reading of the paper. We would like to thank the Core Facility of Medical Research Institute at Wuhan University for confocal microscopy and histological analysis. This study was supported by grants from the National Key R&D Program of China (2017YFA0505600 to GQ), the National Natural Science Foundation of China (81830084 and 81572736 to GQ, 81770177 to HL), National Science Fund for Distinguished Young Scholars (81725013 to GQ), Hubei Provincial Natural Science Fund for Distinguished Young Scholars (2017CFA072 to HL), Hubei Provincial Natural Science Fund for Creative Research Groups (2018CFA018 to GQ), and Innovative Research Grant from Wuhan University (2042017kf0282 to GQ).

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  1. These authors contributed equally: Jingchao Wang, Jue Jiang

Authors and Affiliations

  1. Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China

    Jingchao Wang, Guoliang Qing & Hudan Liu

  2. Medical Research Institute, Wuhan University, 430071, Wuhan, China

    Jingchao Wang, Jue Jiang, Hui Chen, Liyuan Wang, Hao Guo, Daibiao Xiao, Guoliang Qing & Hudan Liu

  3. Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China

    Likun Yang

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Wang, J., Jiang, J., Chen, H. et al. FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma. Oncogene 38, 6737–6751 (2019). https://doi.org/10.1038/s41388-019-0912-5

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