Poster Presentation 32nd Lorne Cancer 2020

RAD51C promoter methylation patterns adapt and influence PARP inhibitor response in ovarian carcinoma patient derived xenografts (#315)

Ksenija Nesic 1 , Rachel M Hurley 2 , Cordelia McGehee 2 , Olga Kondrashova 3 , Saravut J Weroha 2 , Elizabeth Swisher 4 , Alexander Dobrovic 5 , Matthew Wakefield 1 , Scott H Kaufmann 2 , Clare Scott 1
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Mayo Clinic, Rochester, MN, United States of America
  3. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  4. University of Washington, Seattle, WA, United States of America
  5. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia

PARP inhibitor (PARPi) resistance in High Grade Serous Ovarian Carcinoma (HGSOC) can be acquired as a result of restored Homologous Recombination (HR) due to secondary mutations in HR genes (e.g. BRCA1/2 and RAD51C) or loss of BRCA1 promoter methylation (meBRCA1). We have demonstrated that homozygous meBRCA1 can be lost or reverted to heterozygous methylation following platinum-based chemotherapy, resulting in HR-competent, PARPi-resistant tumours. RAD51C promoter methylation (meRAD51C), like meBRCA1, is associated with gene silencing and HR deficiency. We were, therefore, interested in whether meRAD51C zygosity influences platinum and PARPi responses in the same way as meBRCA1.

Two HGSOC Patient Derived Xenograft (PDX) models with RAD51C gene silencing were found to have distinct meRAD51C profiles. Platinum and PARPi-sensitive PDXPH039 had an unusual meRAD51C profile, which we defined as “heterogeneous”, as it was found to represent a mixture of various epialleles with distinct meRAD51C patterns. Platinum-sensitive and PARPi-responsive (stable disease) PDX183 had a homogeneous/homozygous meRAD51C profile. Both models could lose meRAD51C under PARPi (niraparib or rucaparib) or platinum treatment pressure in vivo, with one lineage of PDXPH039 being particularly susceptible to methylation loss (235 tumour aliquots tested). Fully unmethylated RAD51C epialleles restored RAD51C gene expression, and these were selected for under PARPi pressure. Interestingly, ~30% of a cohort of 12 independent meRAD51C HGSOC patient samples were found to have the novel heterogeneous meRAD51C pattern, with remaining cases being homogeneously methylated.

Thus, both homogeneous and heterogeneous patterns of meRAD51C can confer response to platinum and PARPi in HGSOC, but treatment pressure can cause loss of methylation and drug resistance in some tumours. The contrasting PARPi responses of these PDX provide a platform for the study of meRAD51C stability in vivo and may present therapeutic opportunities to improve meRAD51C durability and PARPi responses in HGSOC.