FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma.
Jingchao WangJue JiangHui ChenLiyuan WangHao GuoLikun YangDaibiao XiaoGuoliang QingHudan LiuPublished in: Oncogene (2019)
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.
Keyphrases
- histone deacetylase
- high throughput
- transcription factor
- induced apoptosis
- poor prognosis
- multiple myeloma
- endoplasmic reticulum stress
- drug administration
- cell death
- cell cycle arrest
- newly diagnosed
- end stage renal disease
- long non coding rna
- ejection fraction
- chronic kidney disease
- emergency department
- signaling pathway
- peritoneal dialysis
- cell proliferation
- dna methylation
- young adults
- drug induced
- small molecule
- childhood cancer
- amino acid