TY - JOUR
T1 - Acquired RAD51C promoter methylation loss causes PARP inhibitor resistance in high-grade serous ovarian carcinoma
AU - Nesic, Ksenija
AU - Kondrashova, Olga
AU - Hurley, Rachel M.
AU - McGehee, Cordelia D.
AU - Vandenberg, Cassandra J.
AU - Ho, Gwo Yaw
AU - Lieschke, Elizabeth
AU - Dall, Genevieve
AU - Bound, Nirashaa
AU - Shield-Artin, Kristy
AU - Radke, Marc
AU - Musafer, Ashan
AU - Chai, Zi Qing
AU - Ghamsari, Mohammad Reza Eftekhariyan
AU - Harrell, Maria I.
AU - Kee, Damien
AU - Olesen, Inger
AU - McNally, Orla
AU - Traficante, Nadia
AU - DeFazio, Anna
AU - Bowtell, David D.L.
AU - Swisher, Elizabeth M.
AU - Weroha, S. John
AU - Nones, Katia
AU - Waddell, Nicola
AU - Kaufmann, Scott H.
AU - Dobrovic, Alexander
AU - Wakefield, Matthew J.
AU - Scott, Clare L.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/9/15
Y1 - 2021/9/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85112395804&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112395804&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-21-0774
DO - 10.1158/0008-5472.CAN-21-0774
M3 - Article
C2 - 34321239
AN - SCOPUS:85112395804
SN - 0008-5472
VL - 81
SP - 4709
EP - 4772
JO - Cancer research
JF - Cancer research
IS - 18
ER -