Functional genomics identifies therapeutic targets for MYC-driven cancer

Masafumi Toyoshima, Heather L. Howie, Maki Imakura, Ryan M. Walsh, James E. Annis, Aaron N. Chang, Jason Frazier, B. Nelson Chau, Andrey Loboda, Peter S. Linsley, Michele A. Cleary, Julie R. Park, Carla Grandori

Research output: Contribution to journalArticlepeer-review

189 Citations (Scopus)


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. Weelected 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, 48were 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 ofMYCN-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.

Original languageEnglish
Pages (from-to)9545-9550
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
Publication statusPublished - 2012 Jun 12
Externally publishedYes


  • CECR2
  • PER
  • PES1
  • SHH
  • WNT

ASJC Scopus subject areas

  • General


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