A Small-Molecule Inhibitor Targeting the Mitotic Spindle Checkpoint Impairs the Growth of Uterine Leiomyosarcoma

作者：Shan Weiwei; Akinfenwa Patricia Y; Savannah Kari B; Kolomeyevskaya Nonna; Laucirica Rudolfo; Thomas Dafydd G; Odunsi Kunle; Creighton Chad J; Lev Dina C; Anderson Matthew L^*

来源：Clinical Cancer Research, 2012, 18(12): 3352-3365.

DOI：10.1158/1078-0432.CCR-11-3058

Purpose: Uterine leiomyosarcoma (ULMS) is a poorly understood cancer with few effective treatments. This study explores the molecular events involved in ULMS with the goal of developing novel therapeutic strategies. %26lt;br%26gt;Experimental Design: Genome-wide transcriptional profiling, Western blotting, and real-time PCR were used to compare specimens of myometrium, leiomyoma, and leiomyosarcoma. Aurora A kinase was targeted in cell lines derived from metastatic ULMS using siRNA or MK-5108, a highly specific small-molecule inhibitor. An orthotopic model was used to evaluate the ability of MK-5108 to inhibit ULMS growth in vivo. %26lt;br%26gt;Results: We found that 26 of 50 gene products most overexpressed in ULMS regulate mitotic centrosome and spindle functions. These include UBE2C, Aurora A and B kinase, TPX2, and Polo-like kinase 1 (PLK1). Targeting Aurora A inhibited proliferation and induced apoptosis in LEIO285, LEIO505, and SK-LMS1, regardless of whether siRNA or MK-5108 was used. In vitro, MK-5108 did not consistently synergize with gemcitabine or docetaxel. Gavage of an orthotopic ULMS model with MK-5108 at 30 or 60 mg/kg decreased the number and size of tumor implants compared with sham-fed controls. Oral MK-5108 also decreased the rate of proliferation, increased intratumoral apoptosis, and increased expression of phospho-histone H3 in ULMS xenografts. %26lt;br%26gt;Conclusions: Our results show that dysregulated centrosome function and spindle assembly are a robust feature of ULMS that can be targeted to slow its growth both in vitro and in vivo. These observations identify novel directions that can be potentially used to improve clinical outcomes for this disease. Clin Cancer Res; 18(12); 3352-65.

• 出版日期2012-6-15