A Novel Compound ARN-3236 Inhibits Salt-Inducible Kinase 2 and Sensitizes Ovarian Cancer Cell Lines and Xenografts to Paclitaxel

Abstract

Purpose SIK2 is a centrosome kinase required for mitotic spindle formation and a potential target for ovarian cancer therapy. Here we examine the effects of a novel small molecule SIK2 inhibitor, ARN-3236, on sensitivity to paclitaxel in ovarian cancer. Experimental Design SIK2 expression was determined in ovarian cancer tissue samples and cell lines. ARN-3236 was tested for its efficiency to inhibit growth and enhance paclitaxel sensitivity in cultures and xenografts of ovarian cancer cell lines. SIK2 siRNA and ARN-3236 were compared for their ability to produce nuclear-centrosome dissociation, inhibit centrosome splitting, block mitotic progression, induce tetraploidy, trigger apoptotic cell death and reduce AKT/survivin signaling. Results SIK2 is overexpressed in approximately 30% of high grade serous ovarian cancers. ARN-3236 inhibited growth of 10 ovarian cancer cell lines at an IC50 of 0.8 to 2.6 μM, where the IC50 of ARN-3236 was inversely correlated with endogenous SIK2 expression (Pearson’s r = −0.642, P = 0.03). ARN-3236 enhanced sensitivity to paclitaxel in 8 of 10 cell lines, as well as in SKOv3ip (P = 0.028) and OVCAR8 xenografts. In at least three cell lines a synergistic interaction was observed. ARN-3236 uncoupled the centrosome from the nucleus in interphase, blocked centrosome separation in mitosis, caused prometaphase arrest and induced apoptotic cell death and tetraploidy. ARN-3236 also inhibited AKT phosphorylation and attenuated survivin expression. Conclusions ARN-3236 is the first orally available inhibitor of SIK2 to be evaluated against ovarian cancer in preclinical models and shows promise in inhibiting ovarian cancer growth and enhancing paclitaxel chemosensitivity.

Upregulation of miR‐874‐3p and miR‐874‐5p inhibits epithelial ovarian cancer malignancy via SIK2

“…Although it is possible that the efficacy of miR‐874‐3p and miR‐874‐5p in inhibiting EOC cell chemoresistance is due to blocking SIK2's maintenance of mitotic spindle formation, further research is necessary to determine the mechanism by which SIK2 overexpression restores EOC tumorigenicity. Because SIK 2 promotes the metastasis of ovarian cancer and the resistance to Paclitaxel treatment, which has been confirmed in our study, SIK2 could be used as a good target for ovarian cancer treatment in the future. Overall, this study represents a great step forward in our identification of clinical biomarkers and personalized treatments for EOC that are necessary to reduce the high morbidity and mortality that patients suffer.…”

AMPK-independent LKB1 activity is required for efficient epithelial ovarian cancer metastasis

“…Broadly, these kinases can regulate cell polarity, migration, and metabolism in specific cell contexts [42]. Salt-inducible kinases SIK2 and SIK3 may be required in HGSOC metastasis, but their dependence on LKB1 in this disease is unknown [43][44][45]. AMPK-related kinase ARK5/NUAK1 has been reported to be overexpressed in EOC and implicated in the regulation of EMT [46].…”

SIK2 Promotes Cisplatin Resistance Induced by Aerobic Glycolysis in Breast Cancer Cells through PI3K/AKT/mTOR Signaling Pathway

“…there was also research [22] which found that inhibiting the expression of SIK2 with a specific inhibitor could enhance the sensitivity of ovarian cancer cells to paclitaxel. All indicate that SIK2 plays a vital part in the chemotherapy resistance of tumors, but this is the first time that we have proved that downregulation of SIK2 expression in BC cells can reverse their resistance to cisplatin.…”