Open Access

ARTICLE

SIK2 inhibitor SIC-19 enhances the sensitivity of PARP inhibitors in triple-negative breast cancers and pancreatic cancers

QIAN LI^1,#, SHUNPENG ZHU^1,#, MINGXIAN ZHU², FANG WANG^1,*, JINHUA ZHOU^1,*

1 Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
2 Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215009, China

* Corresponding Authors: FANG WANG. Email: ; JINHUA ZHOU. Email:
# These two authors contributed equally to this work

(This article belongs to the Special Issue: Signaling Pathway Crosstalk in Malignant Tumors: Molecular Targets and Combinatorial Therapeutics)

Oncology Research 2025, 33(7), 1757-1767. https://doi.org/10.32604/or.2025.062539

Received 20 December 2024; Accepted 17 March 2025; Issue published 26 June 2025

Abstract

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.

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Keywords

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