Abstract 4511: CX-5461, a non-genotoxic activator of p53 through selective inhibition of RNA polymerase I for the treatment of hematological cancers

Abstract

Abstract Cancer is characterized by hyperactivation of ribosome biogenesis which depends on increased RNA Polymerase I (Pol I) transcription. Inhibition of Pol I transcription causes nucleolar stress that leads to the release of ribosomal proteins from the nucleolus into the nucleoplasm where they can sequester the p53 inhibitory protein MDM2, causing activation of p53 and induction of apoptosis. The inhibition of Pol I transcription as a therapeutic approach is significant because it impacts two critically balanced processes, proliferation and apoptosis, that regulate cancer cell survival. CX-5461 is a potent and selective inhibitor of Pol I transcription. CX-5461 acts at the initiation stage of Pol I transcription through the disruption of the SL1/rDNA complex. CX-5461 is non-genotoxic and does not inhibit DNA replication, protein translation or RNA Polymerase II transcription. We have previously demonstrated that CX-5461 triggers autophagic cell death in solid tumor cell lines and exhibits antitumor activity in xenograft models, highlighting the importance of Pol I transcription in cancer (Drygin et al. Cancer Res. in press). In preparation for clinical testing we sought to identify the most sensitive indications by evaluating CX-5461 against a panel of genetically diverse cancer cell lines. CX-5461 exhibited a broad range of antiproliferative activity with wild-type (wt) p53 cells derived from hematological malignancies being the most sensitive (median IC50 = 5 nM). Other cell types, i.e. p53 mutated hematological, p53wt and p53 mutated solid tumors were less sensitive to CX-5461 (median IC50s = 94, 164 and 265 nM respectively). In contrast, the median IC50 against normal cells was 5 uM indicating that CX-5461 selectively kills cancer cells. Further molecular characterization revealed that CX-5461 treatment of p53wt hematologic cancer cells inhibited rRNA synthesis, stabilized p53, activated p21, caused cell cycle arrest and induced apoptosis. Chemical inhibition of p53 prevented the induction of apoptosis indicating that CX-5461 acts through activation of p53. Interestingly, while p53 mutations impacted the activity of CX-5461, other genetic alterations known to silence p53 response, i.e. deletion of ARF, did not affect sensitivity to CX-5461 (Bywater et al. 2010 AACR Ann Met Proceedings). Activation of p53 has long been considered an attractive approach for treating cancers because of the surveillance function of p53 to remove abnormal cells via induction of apoptotic cell death. The fact that mutations or deletions of the p53 gene are relatively rare in hematological malignancies, coupled with our data that p53wt hematologic cancer cells are particularly sensitive to CX-5461 provides compelling rationale for evaluating CX-5461 in this patient population. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4511. doi:10.1158/1538-7445.AM2011-4511