A Novel Compound ARN-3236 Inhibits Salt-Inducible Kinase 2 and Sensitizes Ovarian Cancer Cell Lines and Xenografts to Paclitaxel.
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 IC50of 0.8 to 2.6 μmol/L, where the IC50of ARN-3236 was inversely correlated with endogenous SIK2 expression (Pearsonr= -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.Clin Cancer Res; 23(8); 1945-54. ©2016 AACR.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Jinhua
J
Zhou
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Albandri
A
Alfraidi
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Shu
S
Zhang
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Janice M
JM
Santiago-O'Farrill
Arrien Pharmaceuticals, Salt Lake City, Utah.
Venkata Krishna
VK
Yerramreddy Reddy
The Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford, United Kingdom.
Abdulkhaliq
A
Alsaadi
The Nuffield Department of Obstetrics and Gynecology, University of Oxford, Oxford, United Kingdom.
Ahmed A
AA
Ahmed
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Hailing
H
Yang
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jinsong
J
Liu
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Weiqun
W
Mao
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Yan
Y
Wang
National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Osaka, Japan.
Hiroshi
H
Takemori
Arrien Pharmaceuticals, Salt Lake City, Utah.
Hariprasad
H
Vankayalapati
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Zhen
Z
Lu
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. rbast@mdanderson.org.
Robert C
RC
Bast
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C551842:salt-inducible kinase-2, human; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel
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