Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Institute for Advanced Research, Nagoya University, Nagoya, Japan.
Clin Cancer Res. 2022 May 13;28(10):2147-2159. doi: 10.1158/1078-0432.CCR-22-0100.
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.
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.
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.
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.
子宫平滑肌肉瘤是最具侵袭性的妇科恶性肿瘤之一。目前尚未建立有效的治疗策略。本研究旨在基于转录组分析鉴定子宫平滑肌肉瘤的新治疗靶点，并评估新型候选药物的临床前疗效。
使用六例子宫平滑肌肉瘤和三例子宫肌瘤的新鲜冷冻样本进行转录组分析。采用Ingenuity 通路分析（IPA）鉴定子宫平滑肌肉瘤潜在的治疗靶点基因。然后，我们使用三个独立数据集（包括 40 例子宫平滑肌肉瘤）对结果进行验证。随后，使用 SK-UT-1、SK-LMS-1 和 SKN 细胞系检查几种候选基因的选择性抑制剂的抑制作用。
与子宫肌瘤相比，我们在子宫平滑肌肉瘤中发现了 512 个明显失调的基因。IPA 显示，包括 CHEK1 和 PLK1 在内的几个基因的功能被预测在子宫平滑肌肉瘤中被激活。通过体外药物筛选，发现 PLK1 或 CHEK1 抑制剂（BI-2536 或 prexasertib）在纳摩尔浓度下对细胞系表现出优越的抗癌作用，并诱导细胞周期停滞。在 SK-UT-1 荷瘤小鼠中，BI-2536 单药治疗显著抑制肿瘤发生。此外，prexasertib 和顺铂联合治疗抑制肿瘤增殖并延长肿瘤进展时间。
我们发现 PLK1 和 CHEK1 的表达上调；其激酶活性在子宫平滑肌肉瘤中被激活。BI-2536 和 prexasertib 表现出显著的抗癌作用。因此，细胞周期相关激酶可能为子宫平滑肌肉瘤的治疗提供有前途的治疗策略。
