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.
The DDR is a network of signaling pathways that senses and repairs damaged DNA. The central kinases of the DDR, including the ataxia telangiectasia mutated and Rad3-related kinase (ATR) protein, are attractive targets. ATR coordinates the response to replication stress (RS), a driving force of cancer, as well as the result of treatment with certain types of cancer therapy.
Small molecule ATR inhibitors have been in clinical development for several years, and although various novel drugs have come and gone, 2 clear leaders have emerged from the pack. Merck’s M6620 and AstraZeneca’s AZD6738 are both being evaluated in multiple clinical trials across different tumor types.
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.
Several kinases of the phosphatidylinositol kinase-related kinase family of proteins are central to the DDR. Among them, the ATR protein is responsible primarily for the repair of 1 of the major types of DNA damage: single-stranded breaks. In particular, ATR plays a vital role in responding to RS, which occurs if DNA damage accumulates and impedes the fundamental process of DNA replication.
During DNA replication, the double helix is unwound and partially unzipped, creating a fork at the area where replication is taking place. Under RS, damage to the DNA strands can cause replication to slow down or stall, and if the damage goes unrepaired, the fork may collapse, leading to cell death.1-3
Replication protein A binds to single-stranded DNA at sites of damage and the resulting complex is a trigger for ATR recruitment through its binding partner ATR-interacting protein. Full activation of ATR requires a conformational change triggered by the subsequent binding of ATR activator proteins, with evidence suggesting different activator proteins are responsible for initiating different pathways of ATR activation in response to distinct types of DNA damage.
Upon activation, ATR orchestrates a multi-faceted response through activation of numerous downstream effector proteins. Best characterized is the CHK1 kinase; through CHK1, ATR is able to arrest the cell cycle at the S and G2/M phase checkpoints, to reduce RS by blocking global origin “firing” (needed to duplicate a genome’s worth of DNA in a timely and efficient manner) and to trigger the appropriate DNA repair pathways3-5
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.
Paradoxically, the same oncogenic DDR defects cause cancer cells to become highly reliant on intact repair processes—analogous to oncogene addiction—to avoid catastrophic levels of genomic instability that provoke apoptosis.
When combined with other oncogenic alterations that promote a high proliferation rate, cancer cells have to deal with dividing more often and in the presence of greater levels of DNA damage than normal cells, contributing to high levels of RS observed from the earliest stages of tumorigenesis.