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Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Inhibition of CDK Activity02:34

Inhibition of CDK Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
Positive Regulator Molecules02:39

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...

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Related Experiment Video

Updated: Jul 4, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

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 Islam2, Ioanna-Maria Gkotinakou2

  • 1Mass General Brigham Boston, MA United States.

Cancer Research
|July 2, 2026
PubMed
Summary
This summary is machine-generated.

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.

Related Experiment Videos

Last Updated: Jul 4, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

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

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.