Functional genomics identifies therapeutic targets for MYC-driven cancer

摘要

MYC oncogene family members are broadly implicated in human cancers, yet are considered "undruggable" as they encode transcription factors. IV1YC also carries out essential functions in proliferative tissues, suggesting that its inhibition could cause severe side effects. We elected to identify synthetic lethal interactions with c-MYC over-expression (MYC-SL) in a collection of -3,300 druggable genes, using high-throughput siRNA screening. Of 49 genes selected for follow-up, 48 were confirmed by independent retesting and approximately one-third selectively induced accumulation of DNA damage, consistent with enrichment in DNA-repair genes by functional annotation. In addition, genes involved in histone acetylation and tran-scriptional elongation, such as TRRAP and BRD4, were identified, indicating that the screen revealed known MYC-associated pathways. For in vivo validation we selected CSNKIe, a kinase whose expression correlated with MYCN amplification in neuroblastoma (an established MYC-driven cancer). Using RNAi and available small-molecule inhibitors, we confirmed that inhibition of CSNKIe halted growth of /WVOV-arnplif ied neuroblastoma xenografts. CSNK1e had previously been implicated in the regulation of developmental pathways and circadian rhythms, whereas our data provide a previously unknown link with oncogenic MYC. Furthermore, expression of CSNKIe correlated with c-MYC and its transcriptional signature in other human cancers, indicating potential broad therapeutic implications of targeting CSNKIe function. In summary, through a functional genomics approach, pathways essential in the context of oncogenic IV1YC but not to normal cells were identified, thus revealing a rich therapeutic space linked to a previously "undruggable" oncogene.