Poster Presentation 29th Lorne Cancer Conference 2017

Combination drug therapies with the novel RNA polymerase I inhibitor CX-5461 improve efficacy in the treatment of multiple myeloma

Kylee Maclachlan 1 2 , Andrew Cuddihy 2 , Nadine Hein 3 , Carleen Cullinane 2 , Simon Harrison 1 , Gretchen Poortinga 1 2 4 , Ross Hannan 1 2 3 5 6 7
  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 Medicine, St Vincent's Hospital, Melbourne, VIC, Australia
  5. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, Australia
  6. Department of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, VIC, Australia
  7. School of Biomedical Sciences, University of Queensland, Brisbane, QLD, Australia

Background: Inhibiting RNA polymerase I (Pol I) with CX-5461 induces cell death using both p53-dependent and -independent pathways1. In murine models of B-cell lymphoma and acute myeloid leukaemia, treatment with CX-5461 significantly increases survival2-4.

Aims: To determine the efficacy of CX-5461 in the treatment of multiple myeloma (MM), alone and in combination with standard and emerging MM therapies.

Methods: Human myeloma cell lines (HMCLs) were treated with CX-5461 prior to measuring proliferation, cell death and cell cycle distribution. Western blots were performed for markers of DNA damage signaling and cell cycle control. CX-5461 was tested in combination with agents having clinical or preclinical efficacy against MM.

Results: HMCLs demonstrate a range of sensitivity to Pol I inhibition. Sensitivity is not solely dependent on proliferation rate or p53 status. CX-5461 treatment leads to a rapid increase in total and serine-15-phosphorylated p53 protein levels. CX-5461 induces rapid phosphorylation of checkpoint proteins Chk1 and Chk2, even in mutant p53 expressing lines.
The combination of CX-5461 with drugs having differing mechanisms of action (including dexamethasone, everolimus, JQ1, ABT-199 and dinaciclib) shows increased inhibition of proliferation compared to single agents, with carfilzomib and panobinostat producing the best results. In vivo studies using the tVk*MYC model show increased efficacy of CX-5461 in combination with panobinostat.

Summary: Combination therapy delays acquired resistance and increases survival. Our data suggest that the Pol I inhibitor CX-5461 can be combined with a broad spectrum of agents, with carfilzomib and panobinostat showing the most promise.

  1. Drygin et al., Cancer Research 2011
  2. Bywater et al., Cancer Cell 2012
  3. Devlin et al., Cancer Discovery 2016
  4. Hein et al., Blood 2013