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Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT

George Au-Yeung1,2, Franziska Lang1, Walid J Azar1

  • 1Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 25, 2016
PubMed

Insights

Targeting Cyclin E1 (CCNE1) amplified ovarian cancer may involve CDK2 inhibition combined with AKT inhibitors. This novel combination shows promise for treating CCNE1-amplified high-grade serous ovarian cancer (HGSC).

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cyclin E1 (CCNE1) amplification is linked to treatment resistance and poor outcomes in high-grade serous ovarian cancer (HGSC).
  • Targeting CCNE1-amplified cancers and overcoming resistance are critical research areas.

Purpose of the Study:

  • To investigate the dependency of CCNE1-amplified HGSC on CDK2.
  • To identify synergistic drug combinations and strategies to overcome resistance.
  • To explore the relationship between CCNE1 and the AKT pathway in HGSC.

Main Methods:

  • Gene suppression using siRNA and shRNA.
  • Chemical inhibition with dinaciclib (a CDK2 inhibitor).
  • High-throughput compound screening for synergistic drug combinations.
  • Genomic data analysis (TCGA) and functional studies in fallopian tube secretory cells.

Main Results:

  • CDK2 was validated as a therapeutic target, showing sensitivity to gene suppression.
  • Dinaciclib alone did not induce amplicon-dependent sensitivity in HGSC cell lines.
  • Synergistic combinations, including dinaciclib and AKT inhibitors, were identified for CCNE1-amplified HGSC.
  • Coamplification of CCNE1 and AKT2 was observed in TCGA data.
  • Overexpression of Cyclin E1, AKT, and mutant TP53 induced malignant characteristics in fallopian tube cells.

Conclusions:

  • CCNE1-amplified tumors exhibit a dependency on AKT activity.
  • A combination of dinaciclib and AKT inhibitors may selectively target CCNE1-amplified HGSC.
  • This approach offers a potential novel therapeutic strategy for a subset of ovarian cancer patients.

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