Poster Presentation 30th Lorne Cancer Conference 2018

Driving PARP inhibitor resistance in high-grade serous ovarian cancer patient derived xenografts (#193)

Elizabeth Lieschke 1 , Olga Kondrashova 1 2 , Gwo Ho 1 2 3 4 , Ksenjia Nesic 1 2 , Monique Topp 1 5 , Alison Hadley 1 , Robert Holian 1 , Maribel Harrell 6 , Orla McNally 4 , Australian Ovarian Cancer Study Cancer Study 3 , David Bowtell 3 7 , Elizabeth Swisher 6 , Matthew Wakefield 1 8 , Clare Scott 1 2 3
  1. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne
  3. Research Division, Peter MacCallum Cancer Centre, Melbourne
  4. Royal Women’s Hospital, Melbourne
  5. Department of Medicine and Health Sciences, Monash University, Melbourne
  6. University of Washington, Seattle, USA
  7. Department of Pathology, University of Melbourne, Melbourne
  8. Melbourne Bioinformatics, University of Melbourne, Melbourne

Poly-ADP-ribose inhibitor therapy (PARPi) is one of the only targeted therapies available for women with high-grade serous ovarian cancer (HGSOC). PARPi is thought to act via a mechanism of synthetic lethality, targeting only tumour cells with defects in the homologous recombination (HR) DNA repair pathway, including but not limited to mutations in BRCA1 or BRCA2 genes (1). However, despite initial responses observed in patients with HR-deficient cancers, most eventually develop drug-resistant disease (2). Furthermore, even initial responses often greatly differ from patient to patient.


To study the possible mechanisms of pre-existing and acquired PARPi resistance we evaluated response to the PARPi, rucaparib, in a series of chemo-naïve and post-treatment HGSOC patient derived xenograft (PDX) models, with or without HR deficiency. These models included a pair of matched PDX (#19) from the same patient: one chemo-naïve and one obtained following one line of platinum-based therapy. As expected, we observed variable dose-dependent responses to PARPi in chemo-naïve PDX with BRCA1/2 mutations and no responses in chemo-naïve HR competent PDX. We also observed a reduction in PARPi response in the post-platinum treated PDX #19 compared with the matched chemo-naïve PDX. Using this particular model, we aim to drive further PARPi resistance through serial transplantation of the post-PARPi treated PDX samples.


We are addressing pre-existing causes of resistance, such as over-expression of oncogenes, by combining PARPi with drugs such as cell cycle inhibitors, in HR deficient PDX models from different patients. These pre-clinical studies should result in improved outcomes for patients with ovarian cancer by better identifying cancers that are most likely to respond, as well as identifying effective drug combination therapies to overcome the resistance or prevent it from occurring.


  1. Scott C, Kaufmann S, Swisher E. et al. Poly (ADP-ribose) polymerase inhibitors: recent advances and future development. Journal of Clinical Oncology 33(12), 1397-1406 (2015)
  2. Ledermann J, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. New England Journal of Medicine 366, 1382-1392 (2012)