cx-5461 and Hematologic-Neoplasms

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m

Topics: Adult; Aged; Antineoplastic Agents; Benzothiazoles; DNA, Ribosomal; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Naphthyridines; Neoplasm Grading; Neoplasm Staging; RNA Polymerase I; Transcription, Genetic; Young Adult

RNA polymerase I (Pol I)-mediated transcription of the ribosomal RNA genes (rDNA) is confined to the nucleolus and is a rate-limiting step for cell growth and proliferation. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne). Here we demonstrate that CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, our data demonstrate that the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, we show that CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, we propose that acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy.

Topics: Animals; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Benzothiazoles; Cell Enlargement; Cell Nucleolus; Cell Proliferation; Chromatin; Comet Assay; DNA Damage; DNA, Ribosomal; Fibroblasts; Hematologic Neoplasms; Humans; Mice; Mice, Inbred C57BL; Naphthyridines; Nucleic Acid Synthesis Inhibitors; RNA Polymerase I; Signal Transduction; Tumor Suppressor Protein p53

In a preclinical study, the investigational drug CX-5461, which blocks the protein RNA polymerase I, extended survival in mouse models of highly aggressive acute myeloid leukemia and multiple myeloma refractory to standard therapy.

Topics: Animals; Antineoplastic Agents; Benzothiazoles; Hematologic Neoplasms; Mice; Naphthyridines; RNA Polymerase I