Poster Presentation 26th Lorne Cancer Conference 2014

Combined inhibition of ribosome biogenesis and ribosome function cooperate to extend survival in MYC-driven B-cell lymphoma (#131)

Jennifer R Devlin 1 2 , Katherine M Hannan 1 , Nadine Hein 1 , Megan J Bywater 1 , Gretchen Poortinga 1 , Denis Drygin 3 , Sean O'Brien 4 , Carleen Cullinane 1 , Grant A McArthur 1 5 , Ross D Hannan 1 2 5 6 7 , Richard B Pearson 1 2 5 6
  1. Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria, Australia
  3. Cylene Pharmaceuticals, San Diego, CA, USA
  4. Senwha Biosciences, San Diego, CA, USA
  5. Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  6. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia
  7. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia

We recently demonstrated that transcription of the ribosomal genes (rRNA) by RNA Polymerase I (Pol I) can be therapeutically targeted with a novel small molecule, CX-5461, to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B-cell population [1]. The therapeutic effect was a consequence of nucleolar disruption, activation of ribosomal protein (Rp)-MDM2-P53 nucleolar stress response and apoptosis. We have recently launched a first-in-human clinical trial of CX-5461 in patients with hematological malignancies and although our pre-clinical data indicate immense potential of Pol I targeting for cancer therapy, some cancers still develop resistance. We hypothesized that simultaneously targeting the ribosome at multiple steps will extend survival. Thus we tested pharmacological inhibitors of PI3K/AKT/mTOR signalling in combination with CX-5461, as the former pathway is known to potently regulate both translational activity and ribosome biogenesis [2-3].

Using the Eμ-Myc model of B-cell lymphoma we demonstrate that multiple pharmacological inhibitors of the PI3K/AKT/mTOR pathway suppress transcription of the rRNA genes and induce cell death similar to CX-5461. Unexpectedly however, PI3K/AKT/mTOR pathway blockade is not associated with nucleolar disruption, or activation of the Rp/MDM2/p53 nucleolar stress pathway.  This is because inhibition of PI3K/AKT/mTOR signalling suppresses both rRNA synthesis and ribosomal protein synthesis equally and therefore does not increase the pool of free Rps necessary to suppress MDM2 E3 ligase that regulates p53 stability. Furthermore, we demonstrate that combined treatment of Eμ-Myc tumour-bearing mice with CX-5461 and the mTORC1 inhibitor Everolimus delayed relapse and doubled the survival of tumor bearing mice compared to single agent treatment. 

These data demonstrate that dual targeting of the ribosome by selectively inhibiting Pol I transcription and inhibition of key signaling molecules regulating ribosome synthesis and function combine to potently treat MYC driven tumours.  It therefore provides a rationale to combine such drugs in the clinic for the treatment of MYC driven cancer.

  1. [1] Bywater MJ et al., (2012) Cancer Cell 22
  2. [2] Chan JC and Hannan KM et al., (2011) Sci Signalling 4
  3. [3] Pourdehnad M et al., (2013) PNAS 110