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.