Poster Presentation 28th Lorne Cancer Conference 2016

Combined inhibition of RNA Polymerase I and the DNA damage response as a therapeutic strategy for p53 null cancers (#244)

Jaclyn Quin 1 , Keefe Chan 1 , Don Cameron 1 2 , Ricky W Johnstone 1 2 , Grant A McArthur 1 2 , Rick B Pearson 1 2 , Ross D Hannan 2 3 , Elaine Sanij 1 4
  1. Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia
  3. John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia
  4. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia

RNA polymerase I (Pol I) mediated transcription of the ribosomal RNA genes (rDNA) is a rate-limiting step for cell growth and proliferation. rDNA transcription by Pol I produces the 47S ribosomal RNA (rRNA) precursor of the 18S, 5.8S and 28S rRNAs. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo1,2. CX-5461 is currently in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne).

Here we demonstrate that CX-5461 induces p53-independent G1 and G2 checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Furthermore, our data suggest that the combination of drugs targeting ATM/ATR signaling and CX-5461 has a significant improved therapeutic benefit in vivo compared to single agent treatment. Mechanistically, we show CX-5461 prevents Pol I recruitment to the rDNA promoter and promotes an “open” chromatin structure that leads to ATM/ATR signaling and cell cycle arrest associated with attenuated DNA repair and senescence. Thus, we propose that CX-5461 induces a novel stress response that can be targeted to improve therapeutic efficacy.
  1. Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. 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 and Pearson R.B. Cancer Discov. 2015 [Epub] Oct 21.
  2. Bywater M., Poortinga g., Sanij E., Hein N., Peck a., Cullinane C., Wall M., Cluse L., Drygin D., Anderes K., Huser N., Proffitt C., Bliesath J., Haddach M., Schwaebe M., Ryckman D.M. Rice W.G., Lowe S.W., Johnstone R.W., Pearson R.B., McArthur G.A., Hannan R.D. Inhibition of RNA Polymerase I as a Therapeutic Strategy for Cancer-Specific Activation of p53. Cancer Cell. 2012 Jul; 10;22(1):51-65.