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

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 n...

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Autores principales: Yoshida, Kosuke, Yokoi, Akira, Yamamoto, Tomofumi, Hayashi, Yusuke, Nakayama, Jun, Yokoi, Tsuyoshi, Yoshida, Hiroshi, Kato, Tomoyasu, Kajiyama, Hiroaki, Yamamoto, Yusuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365385/
https://www.ncbi.nlm.nih.gov/pubmed/35302600
http://dx.doi.org/10.1158/1078-0432.CCR-22-0100
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author Yoshida, Kosuke
Yokoi, Akira
Yamamoto, Tomofumi
Hayashi, Yusuke
Nakayama, Jun
Yokoi, Tsuyoshi
Yoshida, Hiroshi
Kato, Tomoyasu
Kajiyama, Hiroaki
Yamamoto, Yusuke
author_facet Yoshida, Kosuke
Yokoi, Akira
Yamamoto, Tomofumi
Hayashi, Yusuke
Nakayama, Jun
Yokoi, Tsuyoshi
Yoshida, Hiroshi
Kato, Tomoyasu
Kajiyama, Hiroaki
Yamamoto, Yusuke
author_sort Yoshida, Kosuke
collection PubMed
description 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.
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spelling pubmed-93653852023-01-05 Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma Yoshida, Kosuke Yokoi, Akira Yamamoto, Tomofumi Hayashi, Yusuke Nakayama, Jun Yokoi, Tsuyoshi Yoshida, Hiroshi Kato, Tomoyasu Kajiyama, Hiroaki Yamamoto, Yusuke Clin Cancer Res Translational Cancer Mechanisms and Therapy 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. American Association for Cancer Research 2022-05-13 2022-03-18 /pmc/articles/PMC9365385/ /pubmed/35302600 http://dx.doi.org/10.1158/1078-0432.CCR-22-0100 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Translational Cancer Mechanisms and Therapy
Yoshida, Kosuke
Yokoi, Akira
Yamamoto, Tomofumi
Hayashi, Yusuke
Nakayama, Jun
Yokoi, Tsuyoshi
Yoshida, Hiroshi
Kato, Tomoyasu
Kajiyama, Hiroaki
Yamamoto, Yusuke
Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
title Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
title_full Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
title_fullStr Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
title_full_unstemmed Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
title_short Aberrant Activation of Cell-Cycle–Related Kinases and the Potential Therapeutic Impact of PLK1 or CHEK1 Inhibition in Uterine Leiomyosarcoma
title_sort aberrant activation of cell-cycle–related kinases and the potential therapeutic impact of plk1 or chek1 inhibition in uterine leiomyosarcoma
topic Translational Cancer Mechanisms and Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9365385/
https://www.ncbi.nlm.nih.gov/pubmed/35302600
http://dx.doi.org/10.1158/1078-0432.CCR-22-0100
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