Inhibition of RNA Polymerase I Transcription by CX-5461 As a Therapeutic Strategy for the Cancer-Specific Activation of p53 in MLL-Rearranged Acute Myeloid Leukemias

Autor: Grant A. McArthur, Scott W. Lowe, Nanni Huser, William G. Rice, Ricky W. Johnstone, Ross D. Hannan, Richard B. Pearson, Carlene Cullinane, Hannes Zuber, Amy R. Rappaport, Denis Drygin, Megan J. Bywater, Inge Verbrugge, Nadine Hein, Adele Baker, Kim Stanley, Josh Bliesath, David M. Ryckman
Rok vydání: 2011
Předmět:
Zdroj: Blood. 118:1548-1548
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v118.21.1548.1548
Popis: Abstract 1548 Increased transcription of the ribosomal genes (rDNA) by RNA Polymerase I (Pol I) is a common feature of human cancer1. 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 apoptosis2. We have developed a potent and selective small molecule inhibitor of Pol I transcription (CX-5461) that is non-genotoxic3. When evaluated for anti-proliferative activity against genetically diverse cancer cell lines, CX-5461 exhibited its greatest potency against wild-type (wt) p53 cells derived from hematological malignancies (median IC50 = 12 nM), while the median IC50s in cells derived from p53 mutated hematological, p53wt and p53 mutated solid tumors and normal cells were less sensitive to CX-5461 (median IC50s = 94 nM, 164 nM, 265 nM and 5 mM respectively), indicating CX-5461 selectively kills p53-wild type malignant hematopoietic cells. Consistent with the nucleolar stress model, p53 wt human leukemia cell lines exhibited robust activation of p53 signaling and apoptotic death in response to low nanomolar doses of CX-5461. To explore the therapeutic potential of Pol I transcription inhibition in vivo in hematological malignancies wt for p53 that are refractory to cytotoxic therapies we tested CX-5461 in mouse models of human acute myeloid leukemia (AML) expressing MLL fusion proteins4. Mice transplanted with 5×106 leukemia cells expressing MLL/ENL or MLL/AF9 together with oncogenic NRAS linked to GFP and luciferase biomarkers by virtue of bicistronic retroviral vectors, rapidly developed aggressive leukemia characterized by anemia, leukocytosis, hepatosplenomegaly and within 7–10 days (Mac1+, Gr-1) leukemic cell counts in peripheral blood. Treatment of recipient mice harboring MLL/ENL+NRAS leukemia with CX-5461 (40mg/kg Q3D) significantly increased median survival (17 days for vehicle vs 36 days for drug, P Disclosures: Drygin: Cylene Pharmaceuticals Inc: Employment. Huser:Cylene Pharmaceuticals Inc: Employment. Bliesath:Cylene Pharmaceuticals Inc: Employment. Ryckman:Cylene Pharmaceuticals Inc: Employment. Rice:Cylenen Pharmaceuticals Inc: Employment. Hannan:Cylene Pharmaceuticals Inc: Consultancy.
Databáze: OpenAIRE
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