Poster Presentation 28th Lorne Cancer Conference 2016

Genome-wide RNAi Screen for Synthetic Lethal Interactions with CX-5461 in Ovarian Cancer (#279)

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

More than 1400 Australian women are diagnosed with ovarian cancer (OVCA) every year, which makes ovarian cancer the second most prevalent gynaecological cancer in Australia. Unfortunately, therapeutic options for OVCA patients are still limited. Consequently more than 900 deaths occur per annum [1]. 

Cancer is characterised by unregulated cell growth and proliferation, both of which are dependent on hyperactivation of ribosome biogenesis. Inhibition of ribosome biogenesis using the specific inhibitor of RNA polymerase I (Pol I) dependent transcription of the rDNA genes, CX-5461, has already been reported to have therapeutic potential in a mouse model of MYC driven B-cell lymphoma [2]. Furthermore, recent data show that CX-5461 cooperates with the mTORC1 inhibitor Everolimus in the same model[3]. However the therapeutic potential of CX-5461 in OVCA is yet to be determined.

Our preliminary data utilising a panel of 36 OVCA cell lines suggest that CX-5461 treatment mediates cell cycle arrest (but not apoptosis) in the majority of cells. We hypothesise that identification of genes that can be targeted to cooperate with CX-5461 will define potential drug combinations for the improved treatment of OVCA. Therefore we are performing a genome-wide genetic screen, based on siRNA knockdown, to identify genes that cause synthetic lethal effects with CX-5461 in the high-grade serous ovarian cancer cell line OVCAR4. The primary screen is performed in a 384 well format in the presence of CX-5461 with SMARTpool siRNAs (targeting over 18,100 genes) using cell number (determined by DAPI staining) as a read out. Validated candidates will then be assessed in other ovarian cancer cell lines. Candidates will be prioritised by gene ontology analysis and the availability of relevant small molecule inhibitors, and be further assessed in vitro and in vivo.

  1. (AIHW), A.I.o.H.a.W., Australian Cancer Incidence and Mortality (ACIM) books: Ovarian cancer. 2015: Canberra: AIHW.
  2. Bywater, M.J., et al., Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer cell, 2012. 22(1): p. 51-65.
  3. Devlin, J.R., et al., Combination therapy targeting ribosome biogenesis and mRNA translation synergistically extends survival in MYC-driven lymphoma. (October 21, 2015). Cancer Discovery, 10.1158/2159-8290.CD-14-0673.