Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis

Eric P Kusnadi; Anna S Trigos; Carleen Cullinane; David L Goode; Ola Larsson; Jennifer R Devlin; Keefe T Chan; David P De Souza; Malcolm J McConville; Grant A McArthur; George Thomas; Elaine Sanij; Gretchen Poortinga; Ross D Hannan; Katherine M Hannan; Jian Kang; Richard B Pearson

Journal article

Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis

Eric P Kusnadi, Anna S Trigos, Carleen Cullinane, David L Goode, Ola Larsson, Jennifer R Devlin, Keefe T Chan, David P De Souza, Malcolm J McConville, Grant A McArthur, George Thomas, Elaine Sanij, Gretchen Poortinga, Ross D Hannan, Katherine M Hannan, Jian Kang, Richard B Pearson

EMBO JOURNAL | WILEY | Published : 2020

DOI: 10.15252/embj.2020105111

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Abstract

Elevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNA-damaging cytotoxic drugs. Our previous first-in-human trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA polymerase I (Pol I) transcription, revealed single-agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here, we reveal the molecular basis for this improved efficacy observed in vivo, which is associated with specific suppression of translation of mRNAs..

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University of Melbourne Researchers

Grant McArthur Author Melbourne Medical School

Malcolm McConville Author Biochemistry and Pharmacology

Eric Kusnadi Author The Sir Peter Maccallum Department of Oncology

Richard Pearson 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 Victorian Cancer Agency Mid-Career Research Fellowship

Funding Acknowledgements

The authors thank Kerry Ardley, Susan Jackson, and Rachael Walker for technical assistance with animal experiments. They also thank the Peter MacCallum Cancer Centre Animal Facility, Molecular Genomics Core, FACS Facility, Laboratory Services, and Media Kitchen. The authors would like to acknowledge Dr Maurits Evers (ANU) for his input into the visualization of the next-generation sequencing data. This work was supported by project grants and fellowships (M.J.M. Principal Research Fellowship #1154540, R.D.H. Project Grant #1158732; Principal Research Fellowship #1116999, G.A.M Principal Research Fellowship #1106576, and R.B.P. Project Grants #1053792 and #1102609; Senior Research Fellowship #1058586) and a program grant (R.D.H., G.A.M, and R.B.P. NHMRC Program Grant #1053792) from the National Health and Medical Research Council (NHMRC) of Australia. E.K. was supported by a University of Melbourne International Fee Remission Research Scholarship (MIFRS), a Melbourne International Research Scholarship (MIRS), and a Cancer Therapeutics (CTx) PhD Top Up Scholarship. A.S.T was supported by a University of Melbourne MIFRS and a Melbourne International Engagement Award (MIEA). E.S. is supported by a Victorian Cancer Agency Mid-Career Research Fellowship (MCRF19007).