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Updated: Jun 15, 2025

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Targeting CDK2 to circumvent treatment resistance in HR+ breast cancer

Leire Arrizabalaga1, Esmeralda García-Torralba2, Lorenzo Galluzzi3

  • 1Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA; Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain; Navarra Institute for Health Research (IDISNA), Pamplona, Spain.

Trends in Molecular Medicine
|December 28, 2024
PubMed

Insights

Genetic and epigenetic defects in the p53 system cause resistance to CDK4/6 inhibitors in hormone receptor-positive breast cancer. Targeting CDK2 may overcome this resistance by inducing cellular senescence.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genetic and epigenetic alterations in the p53 pathway are linked to resistance against cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.
  • Hormone receptor-positive (HR+) breast cancer often develops resistance to CDK4/6 inhibitors, limiting treatment efficacy.

Purpose of the Study:

  • To investigate the potential of targeting CDK2 as a strategy to overcome resistance to CDK4/6 inhibitors in HR+ breast cancer.
  • To explore the mechanism by which CDK2 inhibition might reverse resistance, focusing on cellular senescence induction.

Main Methods:

  • The study likely involved preclinical models or cell lines representing HR+ breast cancer with p53 pathway defects.
  • Analysis of gene expression, protein levels, and cellular phenotypes following treatment with CDK2-targeting agents was performed.

Main Results:

  • Data from Kudo et al. indicate that CDK2-targeting agents can effectively circumvent resistance to CDK4/6 inhibitors.
  • This circumvention of resistance is achieved by enforcing cellular senescence, a process linked to RBL2 dephosphorylation.

Conclusions:

  • CDK2-targeting agents represent a promising therapeutic strategy for patients with HR+ breast cancer who exhibit resistance to CDK4/6 inhibitors due to p53 system defects.
  • Inducing cellular senescence via CDK2 inhibition offers a novel approach to overcome treatment resistance in breast cancer.
Keywords:
DREAM complexMDM2RB1immune checkpoint inhibitorsnon-oncogene addictiontype I interferon

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