In 2015, 3 scientists were awarded the Nobel Prize in Chemistry for their work detailing the molecular mechanisms that cells use to repair damaged DNA.1
Numerous repair pathways are activated in response to different types of damage, regulated and coordinated by the broader DNA damage response (DDR) network.
Defects in the DDR are a recognized hallmark of cancer, allowing oncogenic alterations in the genome to go unrepaired and fueling cancerous growth. But cancer cells must maintain a delicate balance to prevent catastrophic levels of DNA damage from triggering cell death, and their heavy reliance on the remaining normal DDR components creates a therapeutically targetable Achilles’ heel (Figure
The proof of concept is the development of PARP inhibitors, which have demonstrated significant efficacy in the treatment of tumors with mutations in the BRCA1/2
genes that encode proteins involved in the repair of double-stranded DNA breaks (DSBs).
Three PARP inhibitors are approved for the treatment of ovarian cancer: olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula). Olaparib and rucaparib received regulatory approval for advanced ovarian cancer with BRCA1/2 mutations confirmed by a companion diagnostic. Olaparib is indicated for patients who have received at least 3 prior treatment regimens; rucaparib, for those who have received 2 or more. All 3 drugs are approved in the maintenance setting earlier in the course of disease in patients who experienced at least a partial response (PR) to chemotherapy, regardless of their BRCA1/2 mutation status.5
Olaparib was also recently approved for the treatment of BRCA1/2-mutant, HER2-negative metastatic breast cancers in patients who have previously received chemotherapy or, in the case of patients with hormone receptor–positive disease, endocrine therapy. Additionally, talazoparib (Talzenna) gained FDA approval for patients with germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer.
Although PARP inhibitors have undeniably proved paradigm changing for the treatment of certain cancers, the overwhelming majority of patients will ultimately develop resistance and disease recurrence via resistance mechanisms that include reversion to wild-type BRCA1/2
As a result, the DDR network, which involves more than 450 proteins, is ripe for continued therapeutic exploitation. Improved understanding of its intricacies is helping advance this goal. They offer up a host of potential therapeutic targets beyond PARP that are now beginning to be explored (Table
Figure. Major DNA Repair Pathways and Potential Therapeutic Targets2-4
Maintaining Genomic Integrity
Cells are constantly under attack from a wide variety of potentially DNA-damaging assailants both within the organism and in the surrounding environment. DNA can be damaged by, among other things, exposure to ultraviolet light, ionizing radiation, toxic chemicals, reactive oxygen species, mechanical stress, and replication errors.
In response, cells have developed a complex network of hundreds of proteins organized into molecular machines that detect damage and either repair it or—if the damage is catastrophic— trigger cell death. Known collectively as the DDR, this network is essential to maintaining the genomic integrity that is vital to the health of the organism.
The specific components of the DDR that are activated depend upon both the specific assault and the type of damage it inflicts, from a simple change in a single base pair to breaks in the DNA.
A diverse range of sensory proteins serve on the frontline, detecting the damaged DNA and setting in motion the DDR pathways that orchestrate the appropriate downstream cellular responses.
Downstream of these damage sensors, the central regulators of the DDR are 3 structurally unique serine/threonine kinases: ataxia telangiectasia mutated (ATM), ataxia telangiectasia and RAD3 related (ATR), and DNA-dependent protein kinase (DNA-PK). ATM and DNA-PK are activated predominantly in response to DSBs, whereas ATR is activated in response to single strand breaks (SSBs), although it does also play a backup role in the DSB response.
These kinases phosphorylate both themselves and a range of downstream targets, further amplifying the damage signal. Among the hundreds of downstream targets for ATM and ATR are key proteins involved in checkpoints at which the cell cycle can be paused to give the cell time to repair the DNA before it is used as a template to synthesize new DNA (G1/S transition checkpoint) or to repair any damage that occurs during DNA replication (S phase checkpoint) or before the cell irreversibly commits to entering mitosis (G2/M checkpoint).6,7