Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

Jennifer R Devlin, Katherine M Hannan, Nadine Hein, Carleen Cullinane, Eric Kusnadi, Pui Yee Ng, Amee J George, Jake Shortt, Megan J Bywater, Gretchen Poortinga, Elaine Sanij, Jian Kang, Denis Drygin, Sean O'Brien, Ricky W Johnstone, Grant A McArthur, Ross D Hannan, Richard B Pearson

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.