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Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma.
Cancer Discov. 2016 Jan; 6(1):59-70.CD

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.

Authors+Show Affiliations

Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. John Curtin School of Medical Research, Australian National University, Acton, Australia. rick.pearson@petermac.org ross.hannan@anu.edu.au.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. John Curtin School of Medical Research, Australian National University, Acton, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. John Curtin School of Medical Research, Australian National University, Acton, Australia. School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.Pimera, Inc., San Diego, California.Senhwa Biosciences, San Diego, California.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. John Curtin School of Medical Research, Australian National University, Acton, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. rick.pearson@petermac.org ross.hannan@anu.edu.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26490423

Citation

Devlin, Jennifer R., et al. "Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma." Cancer Discovery, vol. 6, no. 1, 2016, pp. 59-70.
Devlin JR, Hannan KM, Hein N, et al. Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma. Cancer Discov. 2016;6(1):59-70.
Devlin, J. R., Hannan, K. M., Hein, N., Cullinane, C., Kusnadi, E., Ng, P. Y., George, A. J., Shortt, J., Bywater, M. J., Poortinga, G., Sanij, E., Kang, J., Drygin, D., O'Brien, S., Johnstone, R. W., McArthur, G. A., Hannan, R. D., & Pearson, R. B. (2016). Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma. Cancer Discovery, 6(1), 59-70. https://doi.org/10.1158/2159-8290.CD-14-0673
Devlin JR, et al. Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma. Cancer Discov. 2016;6(1):59-70. PubMed PMID: 26490423.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma. AU - Devlin,Jennifer R, AU - Hannan,Katherine M, AU - Hein,Nadine, AU - Cullinane,Carleen, AU - Kusnadi,Eric, AU - Ng,Pui Yee, AU - George,Amee J, AU - Shortt,Jake, AU - Bywater,Megan J, AU - Poortinga,Gretchen, AU - Sanij,Elaine, AU - Kang,Jian, AU - Drygin,Denis, AU - O'Brien,Sean, AU - Johnstone,Ricky W, AU - McArthur,Grant A, AU - Hannan,Ross D, AU - Pearson,Richard B, Y1 - 2015/10/21/ PY - 2014/06/27/received PY - 2015/10/16/accepted PY - 2015/10/23/entrez PY - 2015/10/23/pubmed PY - 2016/10/14/medline SP - 59 EP - 70 JF - Cancer discovery JO - Cancer Discov VL - 6 IS - 1 N2 - UNLABELLED: 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. SN - 2159-8290 UR - https://www.unboundmedicine.com/medline/citation/26490423/Combination_Therapy_Targeting_Ribosome_Biogenesis_and_mRNA_Translation_Synergistically_Extends_Survival_in_MYC_Driven_Lymphoma_ L2 - http://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=26490423 DB - PRIME DP - Unbound Medicine ER -