OBJECTIVES: Our previous research demonstrated that SIC-19, an innovative inhibitor of salt-inducible kinase 2 (SIK2), effectively reduces SIK2 protein levels through the ubiquitin-proteasome pathway and exhibits synthetic lethal effects with poly ADP-ribose polymerase (PARP) inhibitors in ovarian cancer. However, the role of SIC-19 in triple-negative breast cancer (TNBC) and pancreatic cancer (PC) remains poorly defined. This study aims to investigate whether SIC-19 combined with PARP inhibitors can induce synthetic lethal effects in TNBC and PC. METHODS: Cell lines with high SIK2 expression were identified through Western blot analysis. The combination's impact was evaluated using Cell Counting Kit-8 (CCK8), clone formation, and apoptosis assays, as well as in vivo xenograft models. RESULTS: Our findings indicated that the IC50 of SIC-19 was inversely correlated with endogenous SIK2 expression in TNBC and PC cell lines. SIC-19 modulates the homologous recombination repair pathway by suppressing levels of RAD50-pS635, thereby enhancing the sensitivity of TNBC and PC cells, as well as xenografts, to PARP inhibitors. CONCLUSION: These results underscore the potential of combining PARP inhibitors in combination with SIK2 inhibitors as a novel therapeutic approach to increase PARP inhibition's effectiveness in treating TNBC and PC. This innovative combination therapy represents a promising approach for overcoming resistance mechanisms and improving the outcomes for patients with these challenging malignancies.