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Updated: Jul 4, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

CDK2 Inhibition Exerts RB-Independent Antitumor Activity in CDK4/6 Inhibitor-Resistant HR+/HER2- Breast Cancer

Dejan Juric1, Kazi N Islam1,2, Ioanna-Maria Gkotinakou1,2

  • 1Department of Medicine, Mass General Brigham Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Cancer Research
|July 2, 2026
PubMed

Insights

CDK2 inhibitors show promise for treating hormone receptor-positive metastatic breast cancer resistant to CDK4/6 inhibitors. These CDK2 inhibitors work by impacting DNA replication and cell division, offering a new therapeutic avenue.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) presents a significant clinical challenge in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC).
  • CDK2 inhibitors (CDK2i) are emerging as a potential therapeutic strategy for patients who develop resistance to CDK4/6i therapies.
  • Understanding the mechanisms of resistance and the efficacy of CDK2i is crucial for advancing treatment options in HR+/HER2- MBC.

Purpose of the Study:

  • To evaluate the efficacy of a selective CDK2 inhibitor, PF-07104091, in patients with HR+/HER2- MBC who are resistant to CDK4/6 inhibitors.
  • To investigate the molecular determinants of response and resistance to CDK2 inhibition in this patient population.
  • To explore the mechanistic differences between CDK4/6 inhibitors and CDK2 inhibitors and their potential for synergistic activity.

Main Methods:

  • Analysis of tumor and liquid biopsies from patients treated with PF-07104091.
  • Assessment of patient responses, including disease stabilization and progression.
  • Evaluation of RB (retinoblastoma protein) expression and phosphorylation status.
  • Genomic analysis to determine TP53 status (wild-type vs. mutated).
  • In vitro studies using established and patient-derived cell lines to assess CDK2i effects on cell growth, DNA replication, DNA damage, and mitosis, stratified by RB and p53 status.

Main Results:

  • PF-07104091 monotherapy demonstrated disease stabilization in a cohort of CDK4/6i-resistant HR+/HER2- MBC patients.
  • Treatment responses were observed independently of RB expression and phosphorylation.
  • Non-progressive disease was more frequent in patients with wild-type TP53 tumors.
  • In vitro studies confirmed that CDK2i growth-suppressive effects were independent of RB status in resistant models.
  • CDK2i activity led to reduced DNA replication, increased DNA damage, and inhibited mitotic entry, with p53 expression being critical for growth inhibition.
  • Evidence suggests a shift in CDK dependency from CDK4/6 to CDK2 as cells acquire resistance to CDK4/6i.

Conclusions:

  • CDK2 inhibition represents a viable therapeutic strategy for HR+/HER2- MBC patients with acquired resistance to CDK4/6 inhibitors.
  • The efficacy of CDK2i is not dependent on RB status but is influenced by TP53 status.
  • CDK2 inhibitors exhibit distinct mechanisms of action compared to CDK4/6 inhibitors, suggesting potential for combination therapies to overcome resistance.

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