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Acquired RAD51C Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma
Ksenija Nesic1,2, Olga Kondrashova1,2,3, Rachel M Hurley4
1The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Abstract:
In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (meRAD51C) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the RAD51C promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with RAD51C gene silencing and homologous recombination deficiency (HRD). PDX models lost meRAD51C following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of RAD51C was sufficient to drive PARPi resistance. Genomic copy number profiling of one of the PDX models using SNP arrays revealed that this resistance was acquired independently in two genetically distinct lineages.In a cohort of 12 patients with RAD51C-methylated HGSC, various patterns of meRAD51C were associated with genomic "scarring," indicative of HRD history, but exhibited no clear correlations with clinical outcome. Differences in methylation stability under treatment pressure were also observed between patients, where one HGSC was found to maintain meRAD51C after six lines of therapy (four platinum-based), whereas another HGSC sample was found to have heterozygous meRAD51C and elevated RAD51C gene expression (relative to homozygous meRAD51C controls) after only neoadjuvant chemotherapy.As meRAD51C loss in a single gene copy was sufficient to cause PARPi resistance in PDX, methylation zygosity should be carefully assessed in previously treated patients when considering PARPi therapy. SIGNIFICANCE: Homozygous RAD51C methylation is a positive predictive biomarker for sensitivity to PARP inhibitors, whereas a single unmethylated gene copy is sufficient to confer resistance.
Insights
Homozygous RAD51C methylation predicts PARP inhibitor sensitivity in ovarian cancer. However, even one unmethylated RAD51C copy can cause resistance, highlighting the need for careful assessment in patients.
Area of Science:
- Genomic instability and DNA repair mechanisms in oncology.
- Epigenetic regulation of gene expression in cancer.
- Pharmacogenomics of targeted cancer therapies.
Background:
- Deleterious mutations in RAD51C are known drivers of homologous recombination deficiency (HRD) and predict PARP inhibitor (PARPi) sensitivity in high-grade serous ovarian carcinoma (HGSC).
- RAD51C promoter methylation (meRAD51C) occurs at frequencies similar to mutations, but its impact on PARPi response is not well understood.
Purpose of the Study:
- To investigate the role of RAD51C promoter methylation in HGSC and its association with PARPi sensitivity and resistance.
- To determine if meRAD51C patterns influence homologous recombination deficiency (HRD) and clinical outcomes.
Main Methods:
- Utilized three HGSC patient-derived xenograft (PDX) models with varying meRAD51C patterns to assess PARPi response.
- Analyzed meRAD51C stability and RAD51C gene expression in PDX models and a cohort of 12 HGSC patients treated with PARPi or chemotherapy.
- Employed SNP arrays for genomic copy number profiling in PDX models to understand resistance mechanisms.
Main Results:
- HGSC PDX models with extensive meRAD51C exhibited sensitivity to PARPi, correlating with RAD51C gene silencing and HRD.
- Loss of meRAD51C in a single RAD51C gene copy was sufficient to confer PARPi resistance in PDX models, with resistance emerging independently in distinct lineages.
- In patients, meRAD51C patterns showed associations with genomic scarring (HRD history) but lacked clear clinical outcome correlations; methylation stability varied significantly under treatment pressure.
Conclusions:
- Homozygous RAD51C methylation is a positive predictive biomarker for PARPi sensitivity in HGSC.
- A single unmethylated RAD51C gene copy can lead to PARPi resistance, underscoring the importance of assessing methylation zygosity in previously treated patients.
- Methylation patterns and their stability under therapy are critical factors influencing PARPi response and resistance in HGSC.
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