Related Experiment Video

Updated: Aug 2, 2025

Study of the DNA Damage Checkpoint using Xenopus Egg Extracts
10:55

Study of the DNA Damage Checkpoint using Xenopus Egg Extracts

Published on: November 5, 2012

16.7K

Selective Inhibition of ATM-dependent Double-strand Break Repair and Checkpoint Control Synergistically Enhances the

Audrey Turchick1, Astrid Zimmermann2, Li-Ya Chiu1

  • 1Translational Innovation Platform Oncology and Immuno-Oncology, EMD Serono, Billerica, MA.

Molecular Cancer Therapeutics
|April 20, 2023
PubMed

Insights

Combining ATR and ATM kinase inhibitors enhances cancer cell death by increasing DNA damage and chromosomal defects. This synergistic approach shows promise for improved cancer therapy, particularly in triple-negative breast cancer models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Ataxia telangiectasia and Rad3-related protein (ATR) kinase is crucial for maintaining genomic integrity by preventing replication fork collapse.
  • ATR inhibition induces replication stress, DNA double-strand breaks (DSBs), and cancer cell death, with several inhibitors in clinical trials.
  • Activation of ataxia telangiectasia-mutated (ATM) kinase checkpoints can protect cancer cells from ATR inhibition's lethal effects.

Purpose of the Study:

  • To investigate the functional relationship between ATR and ATM kinases.
  • To explore the therapeutic potential of combining ATR and ATM inhibitors in cancer treatment.

Main Methods:

  • Investigated ATR-ATM functional relationship in cancer cells with functional ATM and p53 signaling.
  • Utilized selective ATR inhibitor (M6620) and selective ATM inhibitors (M3541, M4076).
  • Conducted in vitro and in vivo studies, including patient-derived xenograft models of triple-negative breast cancer.

Main Results:

  • Selective ATR inhibition induced G1-phase arrest in cells with functional ATM/p53.
  • ATM inhibitors suppressed cell-cycle checkpoints and DSB repair, lowering the p53 protective barrier.
  • Combination treatment amplified chromosomal defects, enhanced cancer cell death, and improved efficacy in vivo.
  • Combination therapy with ATR inhibitor M4344 and ATM inhibitor M4076 showed significant improvements in triple-negative breast cancer models.

Conclusions:

  • ATM inhibition synergistically potentiates ATR inhibitor efficacy in cancer cells.
  • Combination therapy targeting both ATR and ATM kinases represents a novel and potentially broad approach to cancer therapy.
  • This combination strategy demonstrated significant improvements in efficacy and survival in preclinical models.

More Related Videos

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors10:33

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

11.4K
Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration08:41

Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration

Published on: December 27, 2024

1.6K

Related Concept Videos

DNA Damage can Stall the Cell Cycle02:37

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...
9.2K
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...
4.8K
The Spindle Assembly Checkpoint02:19

The Spindle Assembly Checkpoint

The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
3.2K
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...
7.7K
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.8K
Restarting Stalled Replication Forks02:37

Restarting Stalled Replication Forks

DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
5.9K