Abstract
MYC oncoproteins deliver a potent oncogenic stimulus in several human cancers, making them major targets for drug development, but efforts to deliver clinically practical therapeutics have not yet been realized. In childhood cancer, aberrant expression of MYC and MYCN genes delineates a group of aggressive tumours responsible for a major proportion of pediatric cancer deaths. We designed a chemical-genetic screen that identifies compounds capable of enhancing proteasomal elimination of MYCN oncoprotein. We isolated several classes of compound that selectively kill MYCN expressing cells and we focus on inhibitors of PI3K/mTOR pathway in this study. We show that PI3K/mTOR inhibitors selectively killed MYCN-expressing neuroblastoma tumor cells, and induced significant apoptosis of transgenic MYCN-driven neuroblastoma tumors concomitant with elimination of MYCN protein in vivo. Mechanistically, the ability of these compounds to degrade MYCN requires complete blockade of mTOR but not PI3 kinase activity and we highlight NVP-BEZ235 as a PI3K/mTOR inhibitor with an ideal activity profile. These data establish that MYCN expression is a marker indicative of likely clinical sensitivity to mTOR inhibition, and provide a rationale for the selection of clinical candidate MYCN-destabilizers likely to be useful for the treatment of MYCN-driven cancers.
Highlights
Aberrant expression of the transcription factorsMYC and MYCN delivers a potent oncogenic stimulus in cancer, making MYC oncoproteins www.impactjournals.com/oncotarget attractive targets for pharmacologic inhibition [1,2,3,4,5,6,7]
Expression constructs encoding FLAGtagged wild type or stabilized (CPD-mutated) MYCN proteins were transfected into human neuroblastoma cells lacking endogenous MYCN expression
Equivalent levels of MYCN expression were achieved in SHEP cells expressing wild-type MYCN (SHEP WT) in comparison to a range of established, tumor-derived neuroblastoma cell lines known to express high-levels of MYCN (Figure S1A)
Summary
MYC and MYCN (a MYC homologue with expression limited to undifferentiated neurons) delivers a potent oncogenic stimulus in cancer, making MYC oncoproteins www.impactjournals.com/oncotarget attractive targets for pharmacologic inhibition [1,2,3,4,5,6,7]. Phosphorylation of conserved T58 and S62 residues within the CPD is regulated by CDK1 (a MAPK target), and by the PI3K/AKT-regulated targets GSK3β and mTOR, respectively [28,29,30]. Aberrant stimulation of MAPK or PI3K pathways contributes to oncogenic stabilization of MYCN in certain cancers. Previous work established that in cancer cell lines, excess PI3K pathway signaling modulates the AKT-regulated targets GSK3β and mTOR, extending the half-life of MYC and outlining a potential pharmacologic approach for targeting MYC stability [28,29,30, 34, 37]
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