Data from c-Jun-NH<sub>2</sub>-kinase-1 Inhibition Leads to Antitumor Activity in Ovarian Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> To show the functional, clinical, and biological significance of c-Jun-NH<sub>2</sub>-kinase (JNK)-1 in ovarian carcinoma.</p><p><b>Experimental Design:</b> Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK <i>in vitro</i> and in experimental models of ovarian cancer was assessed. We studied the role of <i>N</i>-5-[4-(4-methyl piperazine methyl)-benzoylamido]-2-methylphenyl-4-[3-(4-methyl)-pyridyl]-2-pyrimidine amine (WBZ_4), a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer.</p><p><b>Results:</b> We found a significant association of pJNK with progression-free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose-dependent fashion in four ovarian cancer cell lines. <i>In vivo</i>, whereas imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The antitumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights compared with nonsilencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition.</p><p><b>Conclusions:</b> These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the redesigned WBZ_4 compound should be considered for further clinical development. Clin Cancer Res; 16(1); 184–94</p></div>