PARG inhibitors are an emerging class of targeted therapy drugs for cancer treatment. These drugs interfere with a cell’s DNA repair systems, targeting machinery that cancer cells rely on to survive. By disrupting a step in the DNA damage response (DDR) pathway, these inhibitors can cause lethal damage to cancerous cells while largely sparing healthy ones.
The Function of PARG in Cell Health
To maintain genomic stability, cells rely on a complex network of DNA repair pathways. When a DNA break occurs, an enzyme called poly(ADP-ribose) polymerase (PARP) detects it and attaches chains of a molecule called poly(ADP-ribose) (PAR) to proteins at the damage site. This flood of PAR chains acts as a signal, recruiting other proteins to carry out repairs.
This signaling process must be controlled. The enzyme Poly(ADP-ribose) glycohydrolase (PARG) is responsible for this regulation by dismantling the PAR chains once DNA repair is complete. If PARP signals an emergency, PARG is the crew that resolves the crisis, allowing cellular processes to return to normal.
The balance between PARP’s signal creation and PARG’s signal removal is important for cell survival. PARG ensures the DNA repair response is transient, preventing the system from remaining permanently activated. This process, known as poly(ADP-ribosylation), is also involved in regulating chromatin structure and cell death.
How PARG Inhibitors Target Cancer
A PARG inhibitor blocks the PARG enzyme, preventing its clean-up function. When PARG is inhibited, the PAR signal chains created by PARP in response to DNA damage are never removed. This leads to a toxic accumulation of PAR chains at damage sites, severely disrupting cellular activities.
The buildup can cause replication forks, where DNA is copied, to stall and collapse, generating more DNA breaks. This excessive signaling can also trigger a form of cell death known as parthanatos. This approach relies on a concept called synthetic lethality.
Many cancers, like those with BRCA1 or BRCA2 mutations, already have deficient DNA repair pathways. While a normal cell can tolerate the loss of PARG function, a cancer cell with a pre-existing weakness is uniquely vulnerable, leading to its targeted death.
Distinguishing Between PARG and PARP Inhibitors
Both PARG and PARP inhibitors are targeted therapies that disrupt the DNA damage response, but they do so through opposite mechanisms. This distinction is important because their different actions highlight the unique potential of PARG inhibitors.
PARP inhibitors work by preventing the PARP enzyme from creating PAR signal chains. A primary mechanism is “PARP trapping,” where the inhibitor locks the PARP enzyme onto the DNA at the damage site, creating a toxic lesion that blocks repair and replication.
In contrast, PARG inhibitors allow the PARP-driven alarm to sound but prevent it from being turned off. They block the degradation of PAR chains, leading to their toxic accumulation. This mechanistic difference suggests that PARG inhibitors could be effective in cancers that have developed resistance to PARP inhibitors.
Clinical Research and Therapeutic Potential
PARG inhibitors are a newer class of drugs currently being evaluated in clinical trials and are not yet approved as a standard cancer treatment. Early-phase studies focus on determining their safety, dosage, and effectiveness in patients with advanced solid tumors.
Preclinical and early clinical research has shown promise for PARG inhibitors in treating cancers with known defects in DNA repair pathways. This includes certain ovarian, breast, prostate, and lung cancers, especially those with mutations in genes like BRCA1 and BRCA2. One investigational drug, IDE161, is being studied in patients whose tumors have errors in a repair pathway called homologous recombination.
PARG inhibitors can have side effects because they also affect healthy, rapidly dividing cells. Potential side effects observed in studies include bone marrow suppression, which can lead to anemia and thrombocytopenia. Despite these challenges, PARG inhibitors represent a novel strategy for exploiting the vulnerabilities of cancer cells and may provide a new therapeutic option for patients, including those whose tumors have stopped responding to other treatments like PARP inhibitors.