Oral Presentation Australasian RNA Biology and Biotechnology Association 2026 Conference

An RNA-targeted strategy to enhance PARP inhibitor sensitivity in triple-negative breast cancer (142582)

Xue Lu 1 , Maina Bitar 1 2 , Lu Wang 1 3 , Francesco Casciello 1 4 , Juliet French 1 2 3 , Stacey Edwards 1 2 3
  1. QIMR Berghofer, Herston, QLD, Australia
  2. The University of Queensland , Brisbane , QLD, Australia
  3. Queensland University of Technology, Brisbane, QLD, Australia
  4. The Australian National University, Canberra, ACT, Australia

PARP inhibitors (PARPi), either as monotherapy or in combination with chemotherapy, have been shown to improve progression-free survival for patients with homologous recombination (HR)-deficient triple-negative breast cancer (TNBC). However, PARPi monotherapy shows limited effectiveness in HR-proficient tumours, and acquired resistance to PARPi frequently develops. Emerging evidence highlights the critical roles of long noncoding RNAs (lncRNAs) in modulating the DNA damage response. Here, we performed pooled CRISPR/Cas13 RNA screens to identify lncRNAs that regulate DNA repair pathways in TNBC. Our screens identified POLR2J4, an annotated but functionally uncharacterized lncRNA, as one of the top hits.

POLR2J4 is a nuclear lncRNA highly expressed across breast tumour subtypes in TCGA and TNBC cell lines. CRISPR/Cas13d-mediated depletion of POLR2J4 robustly synergised with the PARPi Olaparib, sensitising both HR-deficient and HR-proficient TNBC cells. Antisense oligonucleotide (ASO)-mediated knockdown of POLR2J4 significantly enhanced PARPi sensitivity, reducing olaparib IC50 values by three-fold. Notably, POLR2J4 ASO combined with Olaparib significantly suppressed tumour growth and prolonged survival in patient-derived xenograft (PDX) mouse models.

Mechanistically, POLR2J4 is proposed to scaffold a BRCA1/BCLAF1/SRSF10 RNA-processing complex at the BRCA1 promoter, potentially maintaining co-transcriptional splicing and expression of BRCA1 and a coordinated HR/replication gene module. Consistent with this model, POLR2J4 depletion destabilises BRCA1 promoter activity and expression, coordinately downregulates HR and replication genes, and induces SRSF10-dependent isoform switches across key DNA damage response (DDR) and cell-cycle transcripts. In line with this, POLR2J4 knockdown combined with irradiation markedly reduced RAD51 foci formation, and the resulting HR-deficient, replication-stressed state—marked by S-phase arrest and impaired fork protection—renders these cells sensitive to PARP inhibition. These findings suggest POLR2J4 may act as an upstream lncRNA organiser of a BRCA1-centred splicing axis, whose loss generates a functional BRCAness phenotype, revealing a promising RNA-targeted therapeutic strategy with the potential to extend and redefine the clinical benefit of PARPi beyond HR-deficient TNBC.