The ENST00000539930 transcript predicts sensitivity to PARP inhibitors and clinical prognosis in cancers

Abstract Objectives Synthetic lethality-based cancer therapy, particularly using PARP inhibitors, faces resistance challenges. This study aims to explore the role of gene-specific transcripts due to alternative splicing in PARP inhibitor resistance. Methods This study conducted transcript-level correlation analyses using CCLE and GDSC databases to identify associations between PARP2 splice variants and sensitivity to PARP inhibitors. This study validated the findings through in vitro overexpression experiments in MDA-MB-231 breast cancer cells and organoid models derived from ovarian cancer patients. Cytotoxicity assays were performed to assess olaparib sensitivity, and RNA sequencing was applied to examine transcriptomic changes. Functional enrichment analyses and clinical prognosis evaluations were conducted using TCGA datasets. Results The PARP2 splice variant ENST00000539930 showed a strong correlation with PARP inhibitors sensitivity, outperforming total PARP2 gene expression. Overexpression of ENST00000539930 in MDA-MB-231 cells significantly increased sensitivity to olaparib. Patient-derived ovarian cancer organoids confirmed this correlation (r=−0.43, p=0.04). Transcriptomic analysis revealed that ENST00000539930 expression was associated with activation of RNA splicing and inhibition of DNA repair pathways. Clinically, high ENST00000539930 expression predicted improved survival in breast, ovarian, and pancreatic cancer cohorts (HR=0.62–0.71, p<0.05). Conclusions ENST00000539930 is a splice variant of PARP2 that predicts enhanced sensitivity to PARP inhibitors and favorable clinical outcomes. This study highlights the potential of transcript-specific biomarkers and the importance of alternative splicing in cancer therapy response.