A small-molecule inhibitor targeting the mitotic spindle checkpoint impairs the growth of uterine leiomyosarcoma.

Abstract

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.

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.

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.

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.

• Authors: Weiwei Shan, Patricia Y Akinfenwa, Kari B Savannah, Nonna Kolomeyevskaya, Rudolfo Laucirica, Dafydd G Thomas, Kunle Odunsi, Chad J Creighton, Dina C Lev, Matthew L Anderson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 12 Pg. 3352-65 (Jun 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22535157 (Publication Type: Journal Article)
• Copyright: ©2012 AACR.

Chemical References

• 4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid
• Cyclohexanecarboxylic Acids
• RNA, Small Interfering
• Taxoids
• Thiazoles
• Deoxycytidine
• Docetaxel
• Aurka protein, mouse
• Aurora Kinase A
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Gemcitabine

Topics

• Animals
• Apoptosis (drug effects)
• Aurora Kinase A
• Aurora Kinases
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Centrosome (drug effects, metabolism)
• Cyclohexanecarboxylic Acids (pharmacology)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Docetaxel
• Female
• Gene Expression Profiling
• Humans
• Leiomyoma (drug therapy, pathology)
• Leiomyosarcoma (drug therapy, pathology)
• M Phase Cell Cycle Checkpoints (drug effects)
• Mice
• Mice, Nude
• Myometrium (drug effects)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA Interference
• RNA, Small Interfering
• Taxoids (pharmacology)
• Thiazoles (pharmacology)
• Uterine Neoplasms (drug therapy, pathology)
• Xenograft Model Antitumor Assays
• Gemcitabine