Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53

Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.This work was supported by the National Health and Medical Research Council (NHMRC) of Australia project grants; NHMRC Research Fellowship to R.D.H.; NHMRC Postgraduate Research Scholarship, GSK Postgraduate Research Scholarship and Leukaemia Foundation Postdoctoral Fellowship to M.J.B.; Cancer Council of Victoria Sir Edward Weary Dunlop Clinical Research Fellowship and NHMRC Research Fellowship to G.A.M.; The John T. Reid Charitable Trusts and Mrs. Margaret Ross AM; and in part by Cylene Pharmaceuticals