Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma

Sci Transl Med. 2015 Nov 4;7(312):312ra176. doi: 10.1126/scitranslmed.aab1803.

Abstract

Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT (facilitates chromatin transcription) as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small-molecule curaxin compound CBL0137 markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Carbazoles / pharmacology*
  • Carbazoles / therapeutic use
  • DNA Repair / drug effects
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • High Mobility Group Proteins / antagonists & inhibitors*
  • High Mobility Group Proteins / metabolism
  • Humans
  • Molecular Targeted Therapy
  • Nervous System Neoplasms / drug therapy*
  • Nervous System Neoplasms / metabolism*
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction / drug effects
  • Transcriptional Elongation Factors / antagonists & inhibitors*
  • Transcriptional Elongation Factors / metabolism

Substances

  • Antineoplastic Agents
  • CBLC137
  • Carbazoles
  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • SSRP1 protein, human
  • Transcriptional Elongation Factors