Poster Presentation 30th Lorne Cancer Conference 2018

Understanding mechanisms of PARP inhibitor sensitivity and resistance in high-grade serous ovarian carcinoma (#230)

Ksenija Nesic 1 2 , Olga Kondrashova 1 , Kristy Shield-Artin 1 , Elizabeth Lieschke 1 , Maria I Harrell 3 , Rachel M Hurley 4 , Elizabeth Swisher 3 , Scott H Kaufmann 4 , Matthew Wakefield 1 2 , Clare Scott 1 5
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. University of Melbourne, Parkville, VIC, Australia
  3. University of Washington, Seattle, WA, United States of America
  4. Mayo Clinic, Rochester, MN, United States of America
  5. Royal Women’s Hospital, Melbourne, VIC, Australia

High-grade serous ovarian carcinoma (HGSOC) is the most common subtype of ovarian cancer, and is characterized by frequent loss of homologous recombination (HR) DNA double-strand break (DSB) repair pathway proteins, such as BRCA1 and BRCA2. Despite the promising efficacy of PARP inhibitors (PARPi) in treating HR Deficient (HRD) cancers, less than 50% of BRCA1/2-defective cancers have an objective response.

This project explores the prevalence of well-documented mechanisms of PARPi sensitivity and resistance within our unique HGSOC patient-derived xenograft cohort [1]. Complementing the in vivo work, a panel of HGSOC isogenic cell lines with various DSB repair defects is being used to better understand the role that DSB repair pathways play in PARPi response. Loss of the Classical Non-Homologous End Joining (C-NHEJ) pathway has been shown to cause PARPi resistance in HRD cancer cells, suggesting that this pathway is important for PARPi action [2]. More recently, loss of proteins involved in other DNA DSB repair pathways has been shown to be synthetic lethal with HRD, like PARP1 [3,4]. Using these cell line models, we are studying the similarities and differences between these synthetic lethal relationships, and mapping pathway interactions affecting PARPi sensitivity and resistance in vitro.

Improving the understanding of how DNA repair pathway balance impacts PARPi sensitivity and resistance will provide better insight into which patients are most and least likely to derive benefit from PARPi treatment, and may help in the development of novel therapies for PARPi resistant cancers.

  1. Topp, M. D., Hartley, L., Cook, M., Heong, V., Boehm, E., McShane, L., ... & Etemadmoghadam, D. (2014). Molecular correlates of platinum response in human high‐grade serous ovarian cancer patient‐derived xenografts. Molecular oncology, 8(3), 656-668.
  2. Patel, A. G., Sarkaria, J. N., & Kaufmann, S. H. (2011). Nonhomologous end joining drives poly (ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proceedings of the National Academy of Sciences, 108(8), 3406-3411.
  3. Ceccaldi, R., Liu, J. C., Amunugama, R., Hajdu, I., Primack, B., Petalcorin, M. I., ... & Yusufzai, T. (2015). Homologous-recombination-deficient tumours are dependent on Pol [thgr]-mediated repair. Nature, 518(7538), 258-262.
  4. Lok, B. H., Carley, A. C., Tchang, B., & Powell, S. N. (2013). RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination. Oncogene, 32(30), 3552-3558.