Poster Presentation 28th Lorne Cancer Conference 2016

Combination drug therapies with the novel RNA Polymerase I inhibitor CX-5461 improve efficacy in the treatment of multiple myeloma (#204)

Kylee Maclachlan 1 2 , Andrew Cuddihy 2 , Nadine Hein 3 , Simon Harrison 2 , Ross Hannan 2 3 4 5 6
  1. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  2. Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
  4. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
  5. Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia
  6. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia

Ribosome biogenesis is dysregulated in malignancy, which contributes to cellular transformation and proliferation1. Targeting RNA polymerase I (Pol I) with the novel small molecule inhibitor CX-5461 induces cell death using both p53-dependent and –independent pathways in both haematological and solid tumours2.  In a murine model of B-cell lymphoma, treatment with CX-5461 significantly increased survival3 and it is now in early stage clinical trials.

We are examining the efficacy of CX-5461 in the treatment of multiple myeloma (MM), a malignancy of plasma cells, both alone and in combination with standard and emerging MM therapeutics.

Treating a panel of human myeloma cell lines (HMCLs) with CX-5461 reveals a wide range of sensitivity to Pol I inhibition, as determined by cell death assays and cell cycle distribution.  Our data suggest that sensitivity to CX-5461 is not solely dependent on proliferation rate or TP53 status.

Treatment of HMCLs with CX-5461 leads to a rapid increase in total and serine-15-phosphorylated p53 levels, in line with published data in other malignancies.  Interestingly, an increase in total and phosphorylated Chk1 and Chk2 was also observed, even in mutant p53 expressing cell lines, suggesting a p53-independent mechanism of action involving DNA damage signalling, resulting in activation of S phase and G-cell cycle check points.

The B-cell lymphoma mouse model shows that mice develop resistance to CX-54613, suggesting combination of CX-5461 with a second therapy may provide a further survival advantage. The combination of CX-5461 with the bromodomain inhibitor JQ1, the proteasome inhibitor bortezomib or the histone-deacetylase inhibitor panobinostat shows increased anti-proliferative effect. Studies have commenced to test the effect of these combinations in the VK*MYC murine model of MM.

  1. Hein N, Hannan KM, George AJ, Sanij E, Hannan RD. The nucleolus: an emerging target for cancer therapy. Trends in molecular medicine. 2013;19(11):643-654.
  2. Drygin D, Lin A, Bliesath J, et al. Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth. Cancer research. 2011;71(4):1418-1430
  3. Bywater MJ, Poortinga G, Sanij E, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer cell. 2012;22(1):51-65.