Splicing inhibition hampers pancreatic cancer cell viability by disrupting DNA repair proficiency and mitotic checkpoint integrity

Splicing dysregulation is emerging as a hallmark of cancer, influencing multiple aspects of tumor development. To evaluate the impact of its dysregulation we employed three splicing-targeting drugs: Pladienolide B (PdB), Thailanstatin A (Th.A) and Indisulam (Ind.), all involved in the recognition of 3’ splice site.

Transcriptome analyses in PDAC cell lines and PDOs revealed that splicing inhibition negatively affects the DDR pathway (BRCA1, CHEK1, CHEK2) in homologous recombination-proficient (HRP) PDAC models, representing a promising strategy to enhance their sensitivity to PARP inhibitor (Talazoparib) treatment. Moreover, among the genes that are altered by all three drugs, we observe an enrichment of genes involved in the mitotic checkpoint genes (AURKA, AURKB, CDC25B, KIF21, EZH2).