Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma

Abstract

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

Exploiting DNA repair defects in colorectal cancer

“…In a study of 12 high-grade serous ovarian cancer (HGSOC) patient-derived xenografts and 21 patient samples (ARIEL2 trial), response and resistance to rucaparib were correlated with methylation status of BRCA1. Methylation-mediated silencing of all BRCA1 copies predicted response to rucaparib, while heterozygous methylation was associated with resistance to therapy (Kondrashova et al, 2018).…”

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

“…As such, γH2AX-RAD51 recently showed promising results in breast cancer biopsies, predicting PARP inhibitor sensitivity but also capturing the emergence of secondary resistance [69]. Indeed, the demethylation of RAD51C is associated with mRNA re-expression and development of resistance [70].…”

Inhibition of RNA Polymerase I Transcription Activates Targeted DNA Damage Response and Enhances the Efficacy of PARP Inhibitors in High-Grade Serous Ovarian Cancer

“…To compare the in vivo efficacy of CX-5461 with standard-of-care therapy, we examined the activity of CX-5461 in chemo-naïve HGSOC-PDX (#62) with BRCA1 promoter hypermethylation previously characterized as resistant/refractory to cisplatin and responsive to PARP inhibitor, rucaparib (37,46). Interestingly, despite previously reported rucaparib response, PDX #62 did not respond to olaparib showing progressive disease with an increase in tumor volume of >20% from baseline at 8 days posttreatment ( Figure 7B).…”

“…Individuality and the identity of ovarian cell lines listed in Supplementary Table 1 were routinely confirmed by a polymerase chain reaction (PCR) based short tandem repeat (STR) analysis using six STR loci. Generation of the WEHICS62 cell line from PDX #62 and the OVCAR8 RAD51C KO cell line is described in (37). Cell lines were maintained in culture for a maximum of 8-10 weeks.…”