Cancer cells that manipulate the DNA damage response (DDR) to foster the genomic instability that underlies many of their hallmark processes become heavily reliant on intact pathways for their survival, creating a targetable Achilles heel that can be exploited therapeutically.
Following the paradigm of synthetic lethality established by PARP inhibitors, ATR inhibitors are being evaluated mostly in rational combinations designed to push the cancer cell to the breaking point, but new insights are offering potential inroads into targeting ATR with monotherapy.
Overcoming DNA Damage
Cells are constantly exposed to a host of DNA-damaging assaults, from external threats such as ultraviolet radiation and chemical toxicity to the hazards of replicating the genome for cell division. To maintain genomic integrity, cells evolved the DDR, a highly coordinated network of signaling pathways that sense DNA damage, interact with checkpoints to control the cell cycle, and perform repair.
Figure. Mechanisms of DNA Damage Response Provide Therapeutic Targets3
A Cancer Paradox
Cancer cells have characteristically unstable genomes, which fosters the development of many hallmark processes.6
Given DDR’s seminal role in maintaining genome integrity, defects can promote tumorigenesis. Most common is loss of the G1 cell cycle checkpoint, allowing cancer cells to enter the cell cycle unchecked.
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