In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4355-4355
Abstract:
Abnormalities of the nucleolus, the site of transcription of the ribosomal genes (rDNA) by RNA Polymerase I (Pol I), have been recognized as diagnostic for cancer for more then a century. However, a critical, unresolved question has been whether the accelerated ribosome biogenesis responsible for the nucleolar changes is required for malignancy. Here we show that the PI3K/AKT pathway, deregulated in a high proportion of human tumours, is a critical regulator of ribosome biogenesis. Active AKT is sufficient to drive rRNA synthesis and ribosome biogenesis. Furthermore, AKT cooperates with c-MYC to drive these processes identifying the AKT//MYC network as a master controller of cell growth. Consistent with this concept, AKT activity is required for maximal activation of rRNA synthesis and tumour formation in the Eμ-Myc mouse model of Burkitt's lymphoma (1). Our findings raise the possibility that cancers characterized by unrestrained cellular growth may be vulnerable to therapeutic strategies that target ribosome biogenesis. To directly test this hypothesis, we used a novel selective small molecule inhibitor of Pol I transcription (CX-5461) (2), to show that Pol I can be targeted in vivo to treat tumors in mouse models of lymphoma and leukemia through the activation of p53-dependent apoptosis, while sparing normal hematologic cells. Thus, selective inhibition of Pol I transcription can serve as a novel therapeutic strategy for the treatment of cancer (3). A Phase 1 trial of this first-in-class molecule begins in 2013 at the Peter MacCallum Cancer Centre for patients with haematologic malignancies. Strikingly, allosteric inhibitors of AKT suppress rRNA synthesis independent of p53 and cooperate with CX-5461 in killing Eμ-Myc lymphomas providing a clear rationale for combining these agents in future trials. Citation Format: Megan J. Bywater, Katherine M. Hannan, Gretchen Poortinga, Jennifer R. Devlin, Carleen Cullinane, Denis Drygin, William G. Rice, Daniel Von Hoff, Ricky W. Johnstone, Grant A. McArthur, Ross D. Hannan, Richard B. Pearson. Inhibition of RNA Polymerase I as a strategy to treat cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4355. doi:10.1158/1538-7445.AM2013-4355
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-4355
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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