Novel therapeutic approach for uterine leiomyosarcoma based on transcriptome analysis / 부인종양

ABSTRACT

Uterine leiomyosarcoma (ULMS) is one of the most aggressive gynecological malignancies. In the past decade, novel therapeutic agents such as trabectedin and pazopanib have been approved, but the prognosis of patients remains unsatisfactory. This study aimed to identify potential therapeutic targets for ULMS based on transcriptome analysis. Archival fresh-frozen tumor tissues of 6 ULMS and three leiomyoma samples were used in this study, and total RNA was extracted. First, transcriptome analysis identified 512 significantly differentially expressed genes, and subsequent pathway analysis using IPA software revealed that the functions of cell cycle-related kinases were significantly activated in ULMS. Moreover, our results were validated using 3 independent Gene Expression Omnibus datasets, including 40 ULMS. Therefore, we considered the kinases as novel therapeutic targets and evaluated the anti-cancer effects of several selective inhibitors against them. Most inhibitors exerted a higher anti-cancer effect than pazopanib in three leiomyosarcoma cell lines. Especially, CHEK1 or PLK1 inhibitors strongly induced cell cycle arrest and cell death, and the IC50s were lower nanomolar concentration. Moreover, the inhibitors suppressed the tumor growth in SK-UT-1 bearing mice models. In conclusion, we revealed the unique gene expression profiles of ULMS. CHEK1 and PLK1 are promising therapeutic targets for ULMS, and therefore, further clinical trials are highly anticipated to improve the prognosis of the patients.