Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma

Devlin, Jennifer R., Hannan, Katherine M., Hein, Nadine, Cullinane, Carleen, Kusnadi, Eric, Ng, Pui Yee, George, Amee J., Shortt, Jake, Bywater, Megan J., Poortinga, Gretchen, Sanij, Elaine, Kang, Jian, Drygin, Denis, O'Brien, Sean, Johnstone, Ricky W., McArthur, Grant A., Hannan, Ross D. and Pearson, Richard B. (2016) Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. Cancer Discovery, 6 1: 59-70. doi:10.1158/2159-8290.CD-14-0673


Author Devlin, Jennifer R.
Hannan, Katherine M.
Hein, Nadine
Cullinane, Carleen
Kusnadi, Eric
Ng, Pui Yee
George, Amee J.
Shortt, Jake
Bywater, Megan J.
Poortinga, Gretchen
Sanij, Elaine
Kang, Jian
Drygin, Denis
O'Brien, Sean
Johnstone, Ricky W.
McArthur, Grant A.
Hannan, Ross D.
Pearson, Richard B.
Title Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma
Journal name Cancer Discovery   Check publisher's open access policy
ISSN 2159-8290
2159-8274
Publication date 2016-01-01
Year available 2015
Sub-type Article (original research)
DOI 10.1158/2159-8290.CD-14-0673
Open Access Status Not Open Access
Volume 6
Issue 1
Start page 59
End page 70
Total pages 12
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research
Language eng
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, whereas everolimus induced expression of the proapoptotic 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. Significance: Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma–bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Biomedical Sciences Publications
 
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