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A screening-based approach identifies cell cycle regulators AURKA, CHK1 and PLK1 as targetable regulators of

Yvonne de Jong1, Fairuz Bennani1, Jolieke G van Oosterwijk1

  • 1Department of Pathology, Leiden University Medical Centre, P.O. Box 9600, L1-Q, 2300 RC Leiden, the Netherlands.

Journal of Bone Oncology
|December 14, 2019
PubMed

Insights

This study identified Aurora Kinase A (AURKA), Checkpoint kinase 1 (CHK1), and Polo-like kinase 1 (PLK1) as key survival genes in chondrosarcoma. Inhibiting CHK1 showed the most promise as a therapeutic strategy for chondrosarcoma patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Chondrosarcomas are malignant cartilage tumors resistant to conventional therapies.
  • Kinase inhibitors are effective in various cancers, suggesting potential for chondrosarcoma treatment.

Purpose of the Study:

  • To identify kinase inhibitors targeting chondrosarcoma cell survival.
  • To evaluate novel therapeutic strategies for chondrosarcoma patients.

Main Methods:

  • Conducted siRNA and compound screens targeting 779 and 273 kinases, respectively, in chondrosarcoma cell lines.
  • Validated promising targets (AURKA, CHK1, PLK1) using specific tyrosine kinase inhibitors (MK-5108, LY2603618, Volasertib).
  • Assessed cell viability, cell cycle, apoptosis, and correlated gene expression with patient survival.

Main Results:

  • MK-5108, LY2603618, and Volasertib reduced chondrosarcoma cell viability in a dose-dependent manner, with PLK1 inhibition showing highest sensitivity.
  • CHK1 inhibition enhanced sensitivity to conventional chemotherapy in some cell lines.
  • High CHK1 RNA expression in patient samples correlated with worse overall survival.

Conclusions:

  • AURKA, CHK1, and PLK1 are crucial for chondrosarcoma cell survival.
  • CHK1 inhibition presents the most promising therapeutic target for chondrosarcoma.
  • Further research is needed to validate these findings for clinical application.
Keywords:
AURKACHK1ChondrosarcomaPLK1Screen

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