Journal
NATURE GENETICS
Volume 50, Issue 9, Pages 1240-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0191-z
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Funding
- National Institutes of Health (NIH) [R35-CA210064, R01-CA180692, R35-CA210030, R01-NS088355, R01-GM123511, U01-CA176058]
- Alex's Lemonade Stand Foundation Innovation Award
- Hyundai Hope Grant
- Cookies for Kids Cancer
- Friends for Life Fellowship
- Damon Runyon Cancer Research Foundation [DRG-24-18, DRSG-9-14, DRSG-12-15]
- Alex's Lemonade Stand Foundation Young Investigator Awards
- NIH grant [T32-CA136432]
- Jake Wetchler Foundation
- NATIONAL CANCER INSTITUTE [R01CA180692, R35CA210030, T32CA136432, R35CA210064, U01CA176058] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM123511] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS088355] Funding Source: NIH RePORTER
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Childhood high-risk neuroblastomas with MYCN gene amplification are difficult to treat effectively(1). This has focused attention on tumor-specific gene dependencies that underlie tumorigenesis and thus provide valuable targets for the development of novel therapeutics. Using unbiased genome-scale CRISPR-Cas9 approaches to detect genes involved in tumor cell growth and survival(2-6), we identified 147 candidate gene dependencies selective for MYCN-amplified neuroblastoma cell lines, compared to over 300 other human cancer cell lines. We then used genome-wide chromatin-immunoprecipitation coupled to high-throughput sequencing analysis to demonstrate that a small number of essential transcription factors-MYCN, HAND2, ISL1, PHOX2B, GATA3, and TBX2-are members of the transcriptional core regulatory circuitry (CRC) that maintains cell state in MYCN-amplified neuroblastoma. To disable the CRC, we tested a combination of BRD4 and CDK7 inhibitors, which act synergistically, in vitro and in vivo, with rapid downregulation of CRC transcription factor gene expression. This study defines a set of critical dependency genes in MYCN-amplified neuroblastoma that are essential for cell state and survival in this tumor.
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