|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Durbin, AD, Zimmerman, MW, Dharia, NV, Abraham, BJ, Iniguez, ABalboni, Weichert-Leahey, N, He, S, Krill-Burger, JM, Root, DE, Vazquez, F, Tsherniak, A, Hahn, WC, Golub, TR, Young, RA, A Look, T, Stegmaier, K|
|Date Published||2018 Aug 20|
Childhood high-risk neuroblastomas with MYCN gene amplification are difficult to treat effectively. 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, 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.
|Alternate Journal||Nat. Genet.|