PURPOSE Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibits DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment. EXPERIMENTAL DESIGN Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. A PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) was tested in vitro on gynecologic sarcoma cell lines SK-UT-1, SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in the Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2-knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay. RESULTS Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining DNA repair. Compared with wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and nonhomologous end-joining repairs were impaired. CONCLUSIONS Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacologic inhibition of ATM enhanced the efficacy of the PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.

中文翻译：

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抑制异常过度表达的 Polo 样激酶 4 是治疗 DNA 损伤修复缺陷型子宫平滑肌肉瘤的潜在有效疗法。


目的 子宫平滑肌肉瘤 (LMS) 是一种侵袭性肉瘤，其中一部分表现出 DNA 修复缺陷。 Polo 样激酶 4 (PLK4) 精确调节有丝分裂，其抑制会导致染色体错误分离并增加 DNA 损伤。我们假设 PLK4 抑制是一种有效的 LMS 治疗方法。实验设计 对临床子宫 LMS 样本进行基因组分析，并计算同源重组 (HR) 缺陷评分。在妇科肉瘤细胞系 SK-UT-1、SKN 和 SK-LMS-1 上对含或不含共济失调毛细血管扩张突变 (ATM) 抑制剂 (AZD0156) 的 PLK4 抑制剂 (CFI-400945) 进行体外测试。使用 Balb/c 裸鼠模型中的 SK-UT-1 异种移植模型对研究结果进行了体内验证。还在 BRCA2 敲除 SK-UT-1 细胞系中评估了 CFI-400945 的效果。使用 DNA 损伤报告基因测定分析 DNA 修复机制。结果 子宫 LMS 具有较高的 HR 缺陷评分，过表达 PLK4 mRNA，并显示负责 DNA 修复的基因突变。 CFI-400945 在体外和体内均表现出有效的抗肿瘤活性。 AZD0156 的添加产生了药物协同作用，很大程度上是由于对非同源末端连接 DNA 修复的偏好。与野生型细胞相比，当 HR 和非同源末端连接修复均受损时，BRCA2 敲除对 PLK4 抑制更敏感。结论 由于染色体错误分离和 DNA 损伤增加的影响，具有 DNA 修复缺陷的子宫 LMS 对 PLK4 抑制敏感。 BRCA2 功能丧失或 ATM 的药理学抑制增强了 PLK4 抑制剂的功效。晚期或复发性子宫 LMS 的基因组分析可以指导治疗。