Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53
Menée in vitro et in vivo, cette étude évalue l'intérêt d'une molécule (CX-5641) inhibant l'ARN polymérase I pour le traitement des cancers hématologiques
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. º Hematologic cancer cell survival is dependent on activated Pol I transcription º CX-5461, a selective inhibitor of Pol I, treats hematologic cancers in mice º CX-5461 selectively kills tumor cells by activating p53-dependent apoptosis º CX-5461 shows potent antiproliferative capacity in human hematologic tumor cells