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

作者：Zhou, Jinhua; Alfraidi, Albandri; Zhang, Shu; Santiago-O'Farrill, Janice M.; Reddy, Venkata Krishna Yerramreddy; Alsaadi, Abdulkhaliq; Ahmed, Ahmed A.; Yang, Hailing; Liu, Jinsong; Mao, Weiqun; Wang, Yan; Takemori, Hiroshi; Vankayalapati, Hariprasad; Lu, Zhen; Bast, Robert C., Jr.^*

来源：Clinical Cancer Research, 2017, 23(8): 1945-1954.

DOI：10.1158/1078-0432.CCR-16-1562

• MITOTIC CATASTROPHE
• COACTIVATOR TORC2
• PROSTATE-CANCER
• CENTROSOME
• EXPRESSION
• SIK2
• MICE
• ADENOCARCINOMA
• AMPLIFICATION
• CYTOTOXICITY

Purpose: 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. @@@ 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 the growth of 10 ovarian cancer cell lines at an IC50 of 0.8 to 2.6 mu mol/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. @@@ 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.

• 出版日期2017-4-15
• 单位苏州大学