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Inhibition of Aberrantly Overexpressed Polo-like Kinase 4 Is a Potential Effective Treatment for DNA Damage Repair-Deficient Uterine Leiomyosarcoma.
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.
Afiliación
  • Lee HHY; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Chow KL; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Wong HS; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Chong TY; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Wong AST; School of Biological Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Cheng GHW; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Ko JMK; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Siu HC; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Yeung MCF; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Huen MSY; School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Tse KY; Department of Obstetrics and Gynaecology, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Bray MR; Treadwell Therapeutics, Toronto, Canada.
  • Mak TW; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • Leung SY; Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
  • Ip PPC; Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
Clin Cancer Res ; 30(17): 3904-3918, 2024 Sep 03.
Article en En | MEDLINE | ID: mdl-38848043
ABSTRACT

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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Uterinas / Daño del ADN / Proteínas Serina-Treonina Quinasas / Ensayos Antitumor por Modelo de Xenoinjerto / Reparación del ADN / Leiomiosarcoma Límite: Animals / Female / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Uterinas / Daño del ADN / Proteínas Serina-Treonina Quinasas / Ensayos Antitumor por Modelo de Xenoinjerto / Reparación del ADN / Leiomiosarcoma Límite: Animals / Female / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos