Flash Talk & Poster Presentation 30th Lorne Cancer Conference 2018

A Genome-wide RNAi Screen Identifies Synthetic Lethality of CX-5461 with TOP1 inhibition in Ovarian Cancer (#102)

Shunfei Yan 1 2 , Keefe Chan 2 , Elaine Sanij 2 3 , Carleen Cullinane 1 2 , Kaylene Simpson 1 2 4 , Ross Hannan 1 2 5 6 7 , Rick Pearson 1 2 5 7
  1. Sir Peter MacCallum Department of Oncology, University Of Melbourne, Parkville, Victoria , Australia
  2. Research Division, Peter MacCallum Cancer Centre, MELBOURNE, VIC, Australia
  3. Department of Pathology, University of Melbourne, Parkville, VIC, Australia
  4. Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  5. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia
  6. Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, ANU College of Medicine, Biology and the Environment, Canberra, ACT, Australia
  7. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

High-grade serous ovarian cancer (HGSOC) is common with poor prognosis. Limited therapeutic options are available, and the development of new therapies is of high priority. Using a genome-wide RNAi screening approach, we demonstrate that the combination of the RNA Polymerase I transcription inhibitor (CX-5461) with DNA Topoisomerase 1 (TOP1) inhibition shows cooperative cell killing in multiple HGSOC cell lines. TOP1 inhibitors, such as Topotecan, are currently being used as a second-line therapeutic option for HGSOC. We hypothesise that while acute treatment with CX-5461 inhibits Pol I recruitment to ribosomal DNA, TOP1 inhibition enhances the formation of RNA-DNA hybrids (R-loops) but not other secondary structures such as G4-quadruplex DNA to induce a robust DNA damage response and cell cycle arrest. Combined treatment with CX-5461 and TOP1 inhibitors demonstrates striking efficacy in vivo, which provides evidence for a novel strategy to treat HGSOC patients.