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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

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CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib

Eric Raspé1,2, Katia Coulonval3,2, Jaime M Pita3,2

  • 1WELBIO and Institute of Interdisciplinary Research (IRIBHM), Campus Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium eraspe@ulb.ac.be christos.sotiriou@bordet.be proger@ulb.ac.be.

EMBO Molecular Medicine
|June 2, 2017
PubMed

Insights

Cyclin-dependent kinase (CDK) 4/6 inhibitors like palbociclib show promise for breast cancer. A new gene signature predicts CDK4 T172 phosphorylation, identifying tumors unlikely to respond to these therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • Cyclin D-CDK4/6 complexes are crucial for G1 phase progression and are targeted by therapies like palbociclib for advanced ER-positive breast cancer.
  • Current limitations exist in predicting patient response to CDK4/6 inhibitors, highlighting the need for predictive biomarkers.
  • Activating T172 phosphorylation of CDK4 is a key rate-limiting event signaling active CDK4 and cell cycle initiation.

Purpose of the Study:

  • To investigate the role of CDK4 post-translational modifications, specifically T172 phosphorylation, in breast tumors.
  • To develop and validate a gene expression signature predicting CDK4 modification profiles.
  • To correlate CDK4 T172 phosphorylation and the gene signature with sensitivity to CDK4/6 inhibitors.

Main Methods:

  • Analysis of post-translational modification profiles, including T172 phosphorylation of CDK4, in breast tumors.
  • Development of a gene expression signature to predict CDK4 modification patterns.
  • Correlation studies between CDK4 T172 phosphorylation, gene signature, and sensitivity to the CDK4/6 inhibitor PD0332991 (palbociclib) in cell lines.

Main Results:

  • CDK4 T172 phosphorylation profiles vary across breast tumor subtypes and correlate with tumor risk.
  • A gene expression signature accurately predicted CDK4 modification profiles in both tumors and cell lines.
  • CDK4 T172 phosphorylation showed the strongest correlation with sensitivity to palbociclib in breast cancer cell lines.

Conclusions:

  • The identified gene expression signature can predict CDK4 modification profiles and identify tumors unlikely to respond to CDK4/6 inhibitors.
  • This signature may aid in selecting patients, including those with HER2-positive and basal-like breast tumors, for clinical trials involving CDK4/6 inhibitors.
  • Understanding CDK4 modification patterns offers a potential strategy for personalized therapy selection in breast cancer treatment.
Keywords:
CDK4/6 inhibitorsPD0332991breast cancercyclin‐dependent kinase 4sensitivity biomarker

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