Flash Talk & Poster Presentation 31st Lorne Cancer Conference 2019

Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer (#304)

Elaine Sanij 1 2 , Katherine Hannan 3 , Anthony Xuan 1 , Shunfei Yan 1 , Jessica Ahern 1 , Jinbae Son 1 , Olga Kondrashova 4 , Matthew Wakefield 4 , Keefe Chan 1 , Linda Mileshkin 1 , Kum Kum Khanna 5 , Ross Hannan 1 3 6 7 , Clare Scott 4 , Karen Sheppard 1 7 , Rick Pearson 1 6 7 8
  1. Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
  3. John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia
  4. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
  5. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  6. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic
  7. Department of Biochemistry and Molecular biology, University of Melbourne, Melbourne, VIC, Australia
  8. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia

High-grade serous ovarian cancer (HGSOC) is characterised by frequent alterations of genes involved in the homologous recombination (HR) DNA repair pathway, most frequently BRCA1/21. HR deficient tumours are sensitive to platinum-based chemotherapy and Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi). On this basis, the PARPi olaparib has been approved as a maintenance monotherapy in advanced ovarian cancer patients with germline BRCA mutations following complete or partial response to platinum-based chemotherapy. However, clinical resistance to PARPi and platinum-based therapies is associated with complex mechanisms including acquired HR proficiency and stabilisation of DNA replication forks. Thus, novel therapeutic strategies that circumvent PARPi-resistance will provide a major advance in ovarian cancer therapy.

 

The novel small molecule inhibitor of RNA polymerase I (Pol I) transcription of ribosomal RNA genes CX-54612-5 has shown selective toxicity against BRCA1/2 deficiencies in solid cancer cell lines6 and is currently in phase I clinical trials in haematologic (Peter Mac) and solid cancers (Canada Cancer Trials Group). Here, we demonstrate that CX-5461 exhibits synthetic lethality with HR deficiency in HGSOC cells and has significant therapeutic benefit in HR-deficient HGSOC patient-derived xenograft (PDX) in vivo. 

 

Further, we have demonstrated that CX-5461 activates a DNA damage response (DDR) at rRNA genes leading to MRE11 nuclease-dependent degradation of DNA replication forks. CX-5461 mediated effects on fork destabilisation are distinct from PARPi. Importantly, we demonstrate CX-5461 cooperates with PARPi in exacerbating DNA damage to prolong survival in a HR-deficient HGSOC-patient-derived xenograft (PDX). Further, CX-5461 exhibits significant efficacy in PARPi-resistant HGSOC-PDX. Furthermore, we have identified CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC, highlighting the potential of CX-5461 as an exciting promising therapy against relapsed HGSOC and in combination therapy with PARPi to significantly delay resistance.

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