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

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.

• Authors: Daniel R Carter, Jayne Murray, Belamy B Cheung, Laura Gamble, Jessica Koach, Joanna Tsang, Selina Sutton, Heyam Kalla, Sarah Syed, Andrew J Gifford, Natalia Issaeva, Asel Biktasova, Bernard Atmadibrata, Yuting Sun, Nicolas Sokolowski, Dora Ling, Patrick Y Kim, Hannah Webber, Ashleigh Clark, Michelle Ruhle, Bing Liu, André Oberthuer, Matthias Fischer, Jennifer Byrne, Federica Saletta, Le Myo Thwe, Andrei Purmal, Gary Haderski, Catherine Burkhart, Frank Speleman, Katleen De Preter, Anneleen Beckers, David S Ziegler, Tao Liu, Katerina V Gurova, Andrei V Gudkov, Murray D Norris, Michelle Haber, Glenn M Marshall
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 312 Pg. 312ra176 (Nov 04 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 26537256 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• 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

Topics

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