Abstract 2057: BRCA1 D11q isoform expression impacts PARP inhibitor responses in high grade serous ovarian carcinoma patient derived xenografts

Background: Acquired PARP inhibitor (PARPi) resistance in High Grade Serous Ovarian Carcinoma (HGSOC) commonly occurs via restored homologous recombination DNA repair due to secondary mutations in BRCA1/2. However, overexpression of certain BRCA1 splice isoforms can also contribute to PARPi resistance in HGSOC. This includes the D11q isoform of BRCA1, where deleterious mutations in the 11q region of BRCA1 (exon 10) can be spliced out resulting in a truncated but partially functional BRCA1 protein. Here we describe four HGSOC Patient Derived Xenografts (PDX) with primary BRCA1 11q mutations, where D11q isoform expression has been shown to correlate with platinum and PARPi responses in vivo. Methods: PDX were derived from chemo-naive and pre-treated patients (Table 1). PDX were treated with PARPi rucaparib (300mg/kg) and cisplatin (4mg/kg). D11q isoform expression was assessed using two-step RT-qPCR. DNA sequencing was performed using the BROCA Cancer Risk Panel. Results: PARPi resistant PDX #1032 and #1049 had high D11q expression relative to D11q-high cell line UWB1.289 and the PARPi-responsive models (Table 1). Interestingly, PDX #1049 harboured a second BRCA1 exon 11 donor splice site mutation, shown previously to enhance splicing and increase abundance of the D11q isoform. Indeed, other proximal splice site mutations have been found following relapse in patients with BRCA1 11q mutations post-PARPi. Conclusions: Our work in PDX provides additional functional evidence that BRCA1 D11q expression impacts on PARPi and platinum responses, and is a clinically relevant mechanism of PARPi resistance in a subset of patients with BRCA1 mutations. Whilst high D11q expression can be associated with secondary BRCA1 splice site mutations (PDX #1049), it can also occur in their absence (PDX #1032). Thus, BRCA1 D11q isoform expression should be considered a potential mechanism of PARP-resistance in patients with BRCA1 11q mutations. Table 1.Summary of results.PDX modelPrimary BRCA1 mutationBRCA1 D11q isoform expressionSecondary BRCA1 mutationsOther mutations (BROCA)PDX platinum responsePDX PARPi responsePatient treatments prior to PDX generation#1049Germline BRCA1: c.2475delCVery highBRCA1: c.4096+3A>C (33%) - splice site mutation known to cause increased D11q expressionTP53: c.428_429insCAStable diseaseNon-responsive - progressive disease3 lines of platinum chemotherapy and PARPi#1032Somatic BRCA1: c.1251delTHighNone detectedTP53: c.97-1_97-6del; FANCA: c.3788_3790delR