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

Journal article

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

CANCER DISCOVERY | AMER ASSOC CANCER RESEARCH | Published : 2016

DOI: 10.1158/2159-8290.CD-14-0673

Abstract

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 centr..

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University of Melbourne Researchers

Grant McArthur Author Melbourne Medical School

Jake Shortt Author The Sir Peter Maccallum Department of Oncology

Eric Kusnadi Author The Sir Peter Maccallum Department of Oncology

Richard Pearson Author The Sir Peter Maccallum Department of Oncology

Ricky Johnstone Author The Sir Peter Maccallum Department of Oncology

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Grants

Awarded by National Health and Medical Research Council (NHMRC) of Australia

Awarded by NHMRC Program Grant

Funding Acknowledgements

This work was supported by National Health and Medical Research Council (NHMRC) of Australia project grants (#1043884, 251608, 566702, 166908, 251688, 509087, 400116, 400120, and 566876) and an NHMRC Program Grant (#1053792). Researchers were funded by NHMRC Fellowships (R.W. Johnstone, G.A. McArthur, R.D. Hannan, R.B. Pearson), a Cancer Council of Victoria Sir Edward Weary Dunlop Fellowship (G.A. McArthur), the Lorenzo and Pamela Galli Charitable Trust (G.A. McArthur), and the Leukaemia Foundation of Australia (PhD scholarship to J.R. Devlin).