Acquired RAD51C promoter methylation loss causes PARP inhibitor resistance in high grade serous ovarian carcinoma
Rachel M Hurley,
Cassandra J Vandenberg,
Zi Qing Chai,
Mohammad Reza Eftekhariyan Ghamsari,
Maria I. Harrell,
Australian Ovarian Cancer Study,
David D. Bowtell,
Elizabeth M. Swisher,
S. John Weroha,
Scott H Kaufmann,
Matthew J Wakefield,
Clare L Scott,
Australian Ovarian Cancer Study (AOCS)
Posted 11 Dec 2020
bioRxiv DOI: 10.1101/2020.12.10.419176
Posted 11 Dec 2020
While loss of BRCA1 promoter methylation has been shown to cause PARP inhibitor (PARPi) resistance in high-grade serous ovarian carcinoma (HGSC), the impacts of RAD51C methylation (meRAD51C) remain unresolved. In this study, three PARPi-responsive HGSC patient-derived xenografts (PDX) with RAD51C gene silencing and homologous recombination deficiency were found to have either homogeneous or heterogeneous patterns of meRAD51C. PDX could lose meRAD51C following PARPi treatment (rucaparib/niraparib), where a single unmethylated RAD51C copy was sufficient to drive PARPi-resistance. Genomic profiling revealed this resistance was acquired independently in two distinct PDX lineages. Furthermore, we describe a patient sample where 1/3 RAD51C gene copies lost methylation following neoadjuvant chemotherapy. We show meRAD51C is a positive predictive biomarker for PARPi response and should be screened for routinely in patients. However, methylation loss in a single gene copy is sufficient to cause PARPi resistance and should be carefully assessed in previously treated patients considering PARPi therapy.
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