Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-Myc characterized by elevated Pol I-mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here we demonstrate that coordinated targeting of rDNA transcription and PI3K/AKT/mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYC-driven B-lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma-bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, while everolimus induced expression of the pro-apoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies.
- Received June 27, 2014.
- Revision received October 15, 2015.
- Accepted October 16, 2015.
- Copyright © 2015, American Association for Cancer Research.