The MYC oncoprotein and transcription factor is dysregulated in a majority of human cancers and has been considered a critical target in cancer therapy. However, direct targeting of MYC has so far proven difficult due to the sheer enormity of the pathways and process within a cell that MYC transcriptionally regulates (~10% of all genes). We hypothesized that MYC’s role in harnessing and driving a cell’s growth machinery, i.e. ribosome synthesis, is universally central to MYC’s malignant function. This paradigm predicts that targeting ribosome biogenesis in the nucleolus might provide a platform for therapeutic intervention of MYC-driven cancers. Insulting ribosome biogenesis termed “nucleolar stress” leads to the activation of cell cycle checkpoints resulting in the induction of p53 and subsequently cell cycle arrest or cell death.
We tested the hypothesis that MYC driven tumors would be exquisitely sensitive to activation of nucleolar stress compared to normal cells. To do this we developed a selective small molecule inhibitor of ribosomal gene transcription (CX-5461, Senhwa Bio/Cylene Pharmaceuticals)1 . We demonstrated that nucleolar stress could be exploited as a novel non-genotoxic therapeutic strategy to selectively kill MYC-driven B-cell lymphoma 2 and V-K MYC driven multiple myeloma (Hein and Hannan, unpublished data) both in vitro and in vivo, in a p53 dependent manner.
Although our pre-clinical data indicate immense potential of Pol I targeting as a cancer therapy, Myc-driven cancers still develop resistance. As metabolism is another critical target of the MYC oncogene we hypothesize that targeting ribosome biogenesis and other major targets of MYC activity such as metabolism will reduce the instance of acquired resistance to CX-5461 and extend survival. Most recent data in testing this hypothesis in a panel of Acute Myeloid Leukemia (AML) cell lines with various p53 and MYC genetic backgrounds will be presented.