@Article{or.2025.062539,
AUTHOR = {QIAN LI, SHUNPENG ZHU, MINGXIAN ZHU, FANG WANG, JINHUA ZHOU},
TITLE = {SIK2 inhibitor SIC-19 enhances the sensitivity of PARP inhibitors in triple-negative breast cancers and pancreatic cancers},
JOURNAL = {Oncology Research},
VOLUME = {33},
YEAR = {2025},
NUMBER = {7},
PAGES = {1757--1767},
URL = {http://www.techscience.com/or/v33n7/62637},
ISSN = {1555-3906},
ABSTRACT = { <b>Objectives:</b> 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. <b>Methods:</b> 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 <i>in vivo</i> xenograft models. <b>Results:</b> 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. <b>Conclusion:</b> 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.},
DOI = {10.32604/or.2025.062539}
}