Poster Presentation 29th Lorne Cancer Conference 2017

A Genome-wide RNAi Screen Identifies Synthetic Lethality of CX-5461 with Homologous Recombination Repair Deficiency in Ovarian Cancer (#293)

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

Cancer is characterised by deregulated cell growth and proliferation, both of which are associated with hyperactivation of ribosome biogenesis. Inhibition of ribosome biogenesis using CX-5461, a specific inhibitor of RNA polymerase I-dependent transcription, has shown therapeutic efficacy in a MYC driven B-cell lymphoma mouse model, which is enhanced when used in combination with the mTORC1 inhibitor Everolimus. However, the therapeutic potential of CX-5461 in solid cancers is yet to be determined.

Our preliminary data utilising a panel of 36 ovarian cancer (OVCA) cell lines suggest that acute CX-5461 treatment results in cell cycle arrest and does not induce apoptosis. We hypothesise that the identification of genes that can be targeted to cooperate with CX-5461 will define novel drug combinations for the improved treatment of OVCA. Therefore, we performed a genome-wide RNAi screen to identify synthetic lethal genes with CX-5461 in the high-grade serous ovarian cancer (HGSOC) cell line OVCAR4. Pathway enrichment analysis of the candidate hits showed significant enrichment in the homology-directed DNA repair (HDR) pathway. Synergy with CX-5461 was validated in multiple HGSOC cell lines by both genetic and pharmacological inhibition of HDR pathway components. We are currently investigating the mechanism of this synergy and will further assess efficacy in vivo.

As homologous recombination deficiency (HRD) is observed in up to 50% of HGSOC patients, we suggest that future application of our studies will lead to new therapeutic options to improve the survival of this cohort.