Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma

Author:

Yoshida Kosuke123,Yokoi Akira12ORCID,Yamamoto Tomofumi3,Hayashi Yusuke3,Nakayama Jun3ORCID,Yokoi Tsuyoshi4,Yoshida Hiroshi5ORCID,Kato Tomoyasu6ORCID,Kajiyama Hiroaki1,Yamamoto Yusuke3ORCID

Affiliation:

1. 1Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

2. 2Institute for Advanced Research, Nagoya University, Nagoya, Japan.

3. 3Laboratory of Integrative Oncology, National Cancer Center Research Institute, Tokyo, Japan.

4. 4Division of Clinical Pharmacology, Department of Drug Safety Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan.

5. 5Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.

6. 6Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.

Abstract

Abstract Purpose: Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates. Experimental Design: Transcriptome analysis was performed using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis (IPA) was used to identify potential therapeutic target genes for uterine leiomyosarcoma. Afterward, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using SK-UT-1, SK-LMS-1, and SKN cell lines. Results: We identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The IPA revealed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI-2536 or prexasertib) were found to exert a superior anticancer effect against cell lines at low nanomolar concentrations and induce cell-cycle arrest. In SK-UT-1 tumor-bearing mice, BI-2536 monotherapy remarkably suppressed tumorigenicity. Moreover, the prexasertib and cisplatin combination therapy inhibited tumor proliferation and prolonged the time to tumor progression. Conclusions: We identified upregulated expressions of PLK1 and CHEK1; their kinase activity was activated in uterine leiomyosarcoma. BI-2536 and prexasertib demonstrated a significant anticancer effect. Therefore, cell-cycle–related kinases may present a promising therapeutic strategy for the treatment of uterine leiomyosarcoma.

Funder

JSPS KAKENHI

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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