Title |
Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma
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Published in |
Cancer Discovery, January 2016
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DOI | 10.1158/2159-8290.cd-14-0673 |
Pubmed ID | |
Authors |
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 |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 67% |
Egypt | 1 | 33% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 3 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 101 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 19 | 19% |
Student > Ph. D. Student | 17 | 17% |
Student > Master | 11 | 11% |
Student > Doctoral Student | 10 | 10% |
Student > Bachelor | 7 | 7% |
Other | 15 | 15% |
Unknown | 22 | 22% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 39 | 39% |
Agricultural and Biological Sciences | 17 | 17% |
Medicine and Dentistry | 13 | 13% |
Neuroscience | 2 | 2% |
Immunology and Microbiology | 2 | 2% |
Other | 3 | 3% |
Unknown | 25 | 25% |