Inhibition of Aberrantly Overexpressed Polo-like Kinase 4 Is a Potential Effective Treatment for DNA Damage Repair-Deficient Uterine Leiomyosarcoma

• Published in: Clinical cancer research Vol. 30; no. 17; pp. 3904 - 3918
• Main Authors: Lee, Horace H Y, Chow, Kin Long, Wong, Ho Shing, Chong, Tsz Yan, Wong, Alice S T, Cheng, Grace H W, Ko, Jasmine M K, Siu, Hoi Cheong, Yeung, Maximus C F, Huen, Michael S Y, Tse, Ka Yu, Bray, Mark R, Mak, Tak Wah, Leung, Suet Yi, Ip, Philip P C
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 03.09.2024
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - genetics; Biomarkers; Cell Line, Tumor; DNA Damage - drug effects; DNA Repair - drug effects; Female; Gene Expression Regulation, Neoplastic - drug effects; Gynecological Cancers; Humans; Indoles - pharmacology; Indoles - therapeutic use; Leiomyosarcoma - drug therapy; Leiomyosarcoma - genetics; Leiomyosarcoma - pathology; Mice; Morpholines - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Pyridines; Quinolines; Translational Cancer Mechanisms and Therapy; Translational Research; Uterine Neoplasms - drug therapy; Uterine Neoplasms - genetics; Uterine Neoplasms - pathology; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-23-3720

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. 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. 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. 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.