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

Horace H Y Lee1, Kin Long Chow1, Ho Shing Wong1

  • 1Department of Pathology, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|June 7, 2024
PubMed
Abstract

Insights

Polo-like kinase 4 (PLK4) inhibition shows promise for treating uterine leiomyosarcoma (LMS) with DNA repair defects. Combining PLK4 inhibition with ATM inhibition or in BRCA2-deficient cells enhances anti-tumor effects.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Uterine leiomyosarcoma (LMS) is an aggressive cancer.
  • A subset of LMS exhibits DNA repair defects.
  • Polo-like kinase 4 (PLK4) regulates mitosis and its inhibition causes DNA damage.

Purpose of the Study:

  • To investigate PLK4 inhibition as a potential treatment for uterine LMS.
  • To explore the efficacy of a PLK4 inhibitor (CFI-400945) alone and in combination with an ATM inhibitor (AZD0156).
  • To assess the impact of BRCA2 deficiency on LMS sensitivity to PLK4 inhibition.

Main Methods:

  • Genomic profiling of uterine LMS samples.
  • In vitro testing of CFI-400945 and AZD0156 on gynecologic sarcoma cell lines.
  • In vivo validation using a SK-UT-1 xenograft mouse model.
  • Evaluation in a BRCA2-knockout SK-UT-1 cell line.
  • DNA damage reporter assays to analyze DNA repair mechanisms.

Main Results:

  • Uterine LMS samples showed high homologous recombination (HR) deficiency, PLK4 overexpression, and DNA repair gene mutations.
  • CFI-400945 demonstrated significant antitumor activity in vitro and in vivo.
  • Combination therapy with AZD0156 exhibited synergistic effects, particularly impacting nonhomologous end-joining repair.
  • BRCA2-deficient cells were more sensitive to PLK4 inhibition when both HR and nonhomologous end-joining repair pathways were compromised.

Conclusions:

  • Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition due to induced chromosome missegregation and DNA damage.
  • Pharmacologic ATM inhibition or BRCA2 loss-of-function mutations enhance PLK4 inhibitor efficacy.
  • Genomic profiling can guide therapeutic strategies for advanced or recurrent uterine LMS.

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