RNA polymerase I (Pol I) mediated transcription of the ribosomal RNA genes (rDNA) is a rate-limiting step for cell growth and proliferation. rDNA transcription by Pol I produces the 47S ribosomal RNA (rRNA) precursor of the 18S, 5.8S and 28S rRNAs. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo1,2. CX-5461 is currently in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne).
Here we demonstrate that CX-5461 induces p53-independent G1 and G2 checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Furthermore, our data suggest that the combination of drugs targeting ATM/ATR signaling and CX-5461 has a significant improved therapeutic benefit in vivo compared to single agent treatment. Mechanistically, we show CX-5461 prevents Pol I recruitment to the rDNA promoter and promotes an “open” chromatin structure that leads to ATM/ATR signaling and cell cycle arrest associated with attenuated DNA repair and senescence. Thus, we propose that CX-5461 induces a novel stress response that can be targeted to improve therapeutic efficacy.