title: Functional genomics identifies therapeutic targets for MYC-driven cancer.
abstract: MYC oncogene family members are broadly implicated in human cancers, yet are considered "undruggable" as they encode transcription factors. MYC 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 overexpression (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 transcriptional elongation, such as TRRAP and BRD4, were identified, indicating that the screen revealed known MYC-associated pathways. For in vivo validation we selected CSNK1e, 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 CSNK1e halted growth of MYCN-amplified 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 CSNK1e correlated with c-MYC and its transcriptional signature in other human cancers, indicating potential broad therapeutic implications of targeting CSNK1e function. In summary, through a functional genomics approach, pathways essential in the context of oncogenic MYC but not to normal cells were identified, thus revealing a rich therapeutic space linked to a previously "undruggable" oncogene.
authors.affiliation: Department of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Toyoshima
authors.forename: Heather L
authors.initials: HL
authors.lastname: Howie
authors.forename: Maki
authors.initials: M
authors.lastname: Imakura
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Walsh
authors.forename: James E
authors.initials: JE
authors.lastname: Annis
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Chang
authors.forename: Jason
authors.initials: J
authors.lastname: Frazier
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
authors.forename: Andrey
authors.initials: A
authors.lastname: Loboda
authors.forename: Peter S
authors.initials: PS
authors.lastname: Linsley
authors.forename: Michele A
authors.initials: MA
authors.lastname: Cleary
authors.forename: Julie R
authors.initials: JR
authors.lastname: Park
authors.forename: Carla
authors.initials: C
authors.lastname: Grandori
mesh_terms: D048149:Casein Kinase 1 epsilon / Q000378:metabolism; D016259:Genes, myc; D023281:Genomics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D034741:RNA, Small Interfering
chemical_list: D034741:RNA, Small Interfering; D048149:Casein Kinase 1 epsilon