Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma.
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.


CONCLUSIONS
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.
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Jennifer R
JR
Devlin
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.
Katherine M
KM
Hannan
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. John Curtin School of Medical Research, Australian National University, Acton, Australia.
Nadine
N
Hein
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
Carleen
C
Cullinane
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
Eric
E
Kusnadi
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Pui Yee
PY
Ng
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.
Amee J
AJ
George
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
Jake
J
Shortt
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Megan J
MJ
Bywater
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
Gretchen
G
Poortinga
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
Elaine
E
Sanij
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Jian
J
Kang
Pimera, Inc., San Diego, California.
Denis
D
Drygin
Senhwa Biosciences, San Diego, California.
Sean
S
O'Brien
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.
Ricky W
RW
Johnstone
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.
Grant A
GA
McArthur
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.
Ross D
RD
Hannan
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.
Richard B
RB
Pearson
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D052160:Benzothiazoles / Q000008:administration & dosage* / Q000494:pharmacology; D004275:DNA, Ribosomal / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D000068338:Everolimus / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000628:therapy*; D051379:Mice; D009287:Naphthyridines / Q000008:administration & dosage* / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D052160:Benzothiazoles; C557717:CX 5461; D004275:DNA, Ribosomal; C000715470:MAS1 protein, human; C489427:MYC protein, human; D009287:Naphthyridines; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D000068338:Everolimus