Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes.
Dimitra MavroeidiAnastasia GeorgantaEmmanouil PanagiotouKonstantinos SyrigosVassilis L SouliotisPublished in: International journal of molecular sciences (2024)
The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe. Recent data have shown that the inhibition of ATR can lead to synthetic lethality in ATM-deficient malignancies. In addition, ATR inhibition plays a significant role in the activation of the immune system by increasing the tumor mutational burden and neoantigen load as well as by triggering the accumulation of cytosolic DNA and subsequently inducing the cGAS-STING pathway and the type I IFN response. Taken together, we review stimulating data showing that ATR kinase inhibition can alter the DDR network, the immune system, and their interplay and, therefore, potentially provide a novel strategy to improve the efficacy of antitumor therapy, using ATR inhibitors as monotherapy or in combination with genotoxic drugs and/or immunomodulators.
Keyphrases
- dna damage response
- dna repair
- dna damage
- oxidative stress
- cell cycle arrest
- cell death
- cell cycle
- signaling pathway
- metabolic syndrome
- insulin resistance
- skeletal muscle
- electronic health record
- type diabetes
- clinical trial
- bone marrow
- single molecule
- adipose tissue
- data analysis
- mesenchymal stem cells
- smoking cessation