A novel compound ARN-3236 inhibits salt-inducible kinase 2 and sensitizes ovarian cancer cell lines and xenografts to paclitaxel.

Journal article

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

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 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.

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.

Authors: Zhou, J; Alfraidi, A; Zhang, S; Santiago-O'Farrill, J; Yerramreddy Reddy, V

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for Cancer Research
• Journal: Clinical Cancer Research
• Volume: 23
• Issue: 8
• Pages: 1945-1954
• Publication date: 2016-09-01
• Acceptance date: 2016-09-14
• DOI: 10.1158/1078-0432.ccr-16-1562
• EISSN: 1557-3265
• ISSN: 1078-0432
• Pmid: 27678456
• Language: English
• Keywords: Mice, Nude; Antineoplastic Agents; Gene Knockdown Techniques; Xenograft Model Antitumor Assays; Centrosome; Female; Protein-Serine-Threonine Kinases; Apoptosis; Tissue Array Analysis; Paclitaxel; Drug Synergism; Cell Line, Tumor; Ovarian Neoplasms; Mice; Humans; Immunohistochemistry; Animals