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.

Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity

“…Whether these binding events will be a driving step to carcinogenesis and whether TERT itself, by acting as a cofactor of other transcription factors (16), will contribute to changing the epigenetic state of a cell will also be extremely relevant areas of investigation for future research. Small-molecule inhibition of BRD4, used as an indirect means to target oncogenic MYC functions, is proving to be an exciting new avenue for cancer therapy (67)(68)(69). We believe that the intersection between the telomerase and the MYC signaling pathways described here will have similarly important therapeutic implications.…”

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

“…Analogous cofactors have also been identified, and some are being developed as therapeutic targets (Goga et al 2007;Zuber et al 2011c;Kessler et al 2012;Lin et al 2012a;Toyoshima et al 2012). For example, BRD4 was identified as a therapeutic target for acute myeloid leukemia and other blood cancers by virtue of its ability to sustain MYC transcription, and small molecule BRD4 inhibitors show potent anti-leukemic effects (Dawson et al 2011;Delmore et al 2011;Zuber et al 2011c).…”

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

“…Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24)(25)(26)(27)(28)(29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17).…”