| Summary: | <h4>Purpose</h4> <p>Salt-inducible kinase 2 (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.</p> <h4>Experimental Design</h4> <psik2 ability="" akt="" and="" apoptotic="" arn-3236="" block="" cancer="" cell="" centrosome="" compared="" cultures="" death,="" determined="" dissociation,="" efficiency="" enhance="" expression="" for="" growth="" in="" induce="" inhibit="" its="" lines.="" mitotic="" nuclear–centrosome="" of="" ovarian="" p="" paclitaxel="" produce="" progression,="" reduce="" samples="" sensitivity="" signaling.<="" sik2="" sirna="" splitting,="" survivin="" tested="" tetraploidy,="" their="" tissue="" to="" trigger="" was="" were="" xenografts=""> <h4>Results</h4> <p>SIK2 is overexpressed in approximately 30% of high-grade serous ovarian cancers. ARN-3236 inhibited the growth of 10 ovarian cancer cell lines at an IC50 of 0.8 to 2.6 mmol/L, where the IC50 of ARN-3236 was inversely correlated with endogenous SIK2 expression (Pearson 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.</p> <h4>Conclusions</h4> <p>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.</p></psik2>
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