Poster Presentation 25th Lorne Cancer Conference 2013

Cooperative killing of MYC-driven B-lymphoma cells by inhibitors of the PI3K/AKT/mTOR pathway and RNA Polymerase I transcription (#157)

Jennifer R Devlin 1 , Kate M Hannan 1 , Megan J Bywater 1 , Denis Drygin 2 , William G Rice 2 , Ricky W Johnstone 1 3 , Grant A McArthur 1 3 , Ross D Hannan 1 3 , Richard B Pearson 1 3
  1. Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. Cylene Pharmaceuticals Inc., San Diego, California, USA
  3. Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

The PI3K/AKT/mTOR signalling pathway plays a critical role in regulating ribosome biogenesis, a fundamental cell growth process, which is invariably dysregulated in cancer.  Specifically, AKT signalling promotes transcription of the ribosomal RNA (rRNA) genes by RNA Polymerase I (Pol I), which is a rate-limiting step in ribosome biogenesis [1].  We used the Eμ-MYC model of B-cell lymphoma to demonstrate that inhibitors of the PI3K/AKT/mTOR pathway potently suppressed transcription of the rRNA genes and induced apoptosis to equivalent levels as the specific Pol I transcription inhibitor CX-5461.  Remarkably, suppression of Pol I transcription by targeting the upstream signalling with PI3K/AKT/mTOR inhibitors resulted in apoptosis that was not associated with nucleolar stress nor acute activation of p53. This is in striking contrast to CX-5461, which targets Pol I machinery directly, and was previously shown to trigger nucleolar stress and to rely on intact p53 function for its anti-tumor activity in Eμ-MYC B-cell lymphoma in vivo [2].  Furthermore,treatment with PI3K/AKT/mTOR pathway inhibitors, but not CX-5461, up-regulated the expression of the pro-apoptotic BH3-only protein BMF. Collectively these results provide evidence that differential inhibition of Pol I transcription by PI3K/AKT/mTOR pathway inhibitors (upstream) and CX-5461 (direct) induces apoptosis via distinct mechanisms and could therefore have enhanced therapeutic potential in combination.  Indeed, combined treatment of Eμ-MYC cells in vitro with AKTi-1/2 and CX-5461 resulted in enhanced induction of apoptosis, providing a rational to combine these inhibitors in the clinic for the treatment of cancer.

  1. Chan et al., (2011) Science Signaling 4 (188), ra56
  2. Bywater et al., (2012) Cancer Cell 22, 51–65