XYL-1 and Olaparib Synergistically Inhibit the Growth of Pancreatic Cancer by Suppressing the SCD1/BRCA1 Signaling Pathway.

PARP1/2 inhibitors have received FDA approval for pancreatic cancer harboring BRCA1/2 mutations and homologous recombination (HR) deficiency; however, their limited indications restrict their broader clinical application. Previous studies have demonstrated that PARP7, a member of the PARP family, enhances tumor sensitivity to PARP1/2 inhibition. However, the mechanisms underlying their synergistic effects in pancreatic cancer remain unclear. Herein, we found that combined inhibition of PARP1/2 and PARP7 using Olaparib and XYL-1 significantly inhibited the proliferation of SW1990 and CFPAC cells compared with either single agent. Furthermore, XYL-1 and Olaparib cooperatively caused DNA damage and induced cell apoptosis in SW1990 cells. Consistently, combined treatment with XYL-1 and Olaparib significantly suppressed SW1990 tumor growth compared with single-agent treatment in mouse xenograft models, accompanied by elevated levels of phosphorylated H2AX in tumor tissues. Notably, bioinformatic analyses and mechanistic studies identified SCD1 and BRCA1 as key mediators of the synergistic antitumor effects of XYL-1 and Olaparib. More importantly, the combination of XYL-1 and Olaparib synergistically downregulated the expression of SCD1 and BRCA1, thereby impairing the HR-mediated DNA repair pathway. Collectively, these findings suggest that dual targeting of PARP7 and PARP1/2 may represent a promising therapeutic strategy for BRCA-proficient pancreatic cancer.