Simultaneous cotargeting of ATR and RNA Polymerase I transcription demonstrates synergistic antileukemic effects on acute myeloid leukemia

摘要

Continued development of novel therapeutic agents is criticalto improve the survival of patients with acute myeloid leukemia(AML). RNA Polymerase I (Pol I)-mediated transcription andribosomal biogenesis become dysregulated, thereby allowingsynthesis of necessary substrates to support uncontrolled cancercell proliferation1. The Pol I transcription rate is higher in AML cellsthan nonleukemic myeloid precursors2, suggesting Pol I transcriptionas a therapeutic target for AML. CX-5461 is a potent Pol Itranscription inhibitor and stabilizer of the DNA G-quadruplexstructure, which causes G2/M-phase arrest via the ATR (ataxiatelangiectasia and Rad3-related protein)-mediated DNA damageresponse (DDR)3–5. Therefore, we hypothesized that the ATRselectiveinhibitor AZD6738 would synergistically enhance CX5461-inducedcell death via abolishment of the ATR-mediatedDDR.