secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out the mutation-containing exon, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary splice site mutations (SSMs), predicted to drive exon skipping. Predictions were confirmed using qRT-PCR, RNA sequencing, western blots and minigene modelling. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials. We demonstrate that SSMs drive exon 11 skipping and PARPi resistance, and should be clinically monitored, along with frame-restoring secondary mutations.