Related Experiment Video

Updated: May 21, 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

Modification of the DNA damage response by therapeutic CDK4/6 inhibition

Jeffry L Dean1, A Kathleen McClendon, Erik S Knudsen

  • 1Kimmel Cancer Center, Philadelphia, Pennsylvania, USA.

The Journal of Biological Chemistry
|June 27, 2012
PubMed

Insights

CDK4/6 inhibition in triple-negative breast cancer (TNBC) antagonizes chemotherapy by causing cell cycle arrest. This arrest hinders DNA damage induction and shifts DNA repair from accurate homologous recombination to error-prone non-homologous end joining.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The RB/E2F pathway is crucial for cell signaling, integrating various pathways.
  • E2F-mediated transcription plays a role in DNA damage response, repair, and apoptosis.
  • Triple-negative breast cancer (TNBC) presents unique therapeutic challenges.

Purpose of the Study:

  • To investigate the impact of CDK4/6 inhibition and RB activation on TNBC response to therapeutics.
  • To understand how repressing E2F activity affects DNA damage and repair mechanisms in TNBC.

Main Methods:

  • Utilized CDK4/6 inhibitors to induce RB activation and cell cycle arrest in TNBC models.
  • Administered cytotoxic agents (taxanes, anthracyclines) in combination with CDK4/6 inhibitors.
  • Employed gamma irradiation (IR) to assess direct DNA damage and repair pathway shifts.

Main Results:

  • CDK4/6 inhibition antagonized cytotoxic agents by preventing DNA damage and cell death, dependent on RB.
  • Cell cycle arrest induced by CDK4/6 inhibitors shifted DNA repair from homologous recombination (HR) to non-homologous end joining (NHEJ).
  • The overall rate of DNA repair was not altered, but the mechanism shifted towards error-prone NHEJ.

Conclusions:

  • CDK4/6 inhibition can antagonize conventional cytotoxic therapies in TNBC.
  • This inhibition promotes the use of error-prone DNA repair pathways, potentially driving disease progression.
  • Findings highlight the complex interplay between cell cycle control and DNA repair in cancer therapy.

More Related Videos

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts10:27

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Published on: July 25, 2020

Using Next Generation Sequencing to Identify Mutations Associated with Repair of a CAS9-induced Double Strand Break Near the CD4 Promoter06:59

Using Next Generation Sequencing to Identify Mutations Associated with Repair of a CAS9-induced Double Strand Break Near the CD4 Promoter

Published on: March 31, 2022

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...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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...
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...