Transient splicing inhibition causes persistent DNA damage and enhances chemotherapy vulnerability in homologous recombination proficient triple-negative breast cancer

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Most TNBCs are initially sensitive to DNA damaging chemotherapy, a substantial fraction acquire resistance to treatments and progress to advanced stages associated with poor prognosis. We identify the spliceosome U2 small nuclear ribonucleoprotein (snRNP) complex as a modulator of chemotherapy efficacy in TNBC. Transient treatment with U2snRNP inhibitors induced a persistent DNA damage in TNBC cells and patient-derived organoids (PDOs), regardless of their homologous recombination proficiency. Transcriptome analyses revealed that U2snRNP inhibition causes a pervasive deregulation of genes involved in the DNA damage response (DDR), which relied on their genomic structure characterized by a high number of small exons. Importantly, a pulse of splicing inhibition was sufficient to elicit long-lasting repression of DDR proteins and to enhance the cytotoxic effect of platinum-based drugs and poly ADP-ribose polymerase inhibitors (PARPi) in multiple TNBC models. These findings identify the U2snRNP as an actionable target that can be exploited to enhance chemotherapy efficacy in TNBCs.