What is PARP?
Poly (ADP-ribose) polymerase, commonly known as
PARP, is a family of proteins involved in a number of cellular processes, primarily the repair of DNA damage. PARP enzymes detect DNA strand breaks and signal for their repair by adding poly (ADP-ribose) chains to themselves and other proteins involved in the DNA repair process. This modification is crucial for maintaining the integrity of the genome.
Role of PARP in DNA Repair
PARP plays a pivotal role in the
base excision repair (BER) pathway, a mechanism that fixes single-strand breaks in DNA. When DNA damage occurs, PARP binds to the broken DNA and becomes activated. It then facilitates the recruitment of other DNA repair proteins to the site of damage. This process is essential for preventing the accumulation of DNA damage, which can lead to cell death or cancer if left unrepaired.
PARP Inhibitors in Cancer Treatment
PARP inhibitors (PARPi) are a class of drugs that block the activity of PARP enzymes. These inhibitors have shown great promise in treating cancers that are deficient in other DNA repair mechanisms, particularly those involving mutations in the
BRCA1 or
BRCA2 genes. BRCA-mutated cells are already compromised in their ability to repair double-strand breaks through homologous recombination, making them highly dependent on PARP-mediated single-strand break repair. Inhibiting PARP in these cells leads to an accumulation of DNA damage, ultimately resulting in cell death—a concept known as "synthetic lethality."
Clinical Applications of PARP Inhibitors
PARP inhibitors have been approved for the treatment of certain types of
breast and
ovarian cancers, particularly those that are BRCA-mutated. The first PARP inhibitor to receive FDA approval was
Olaparib in 2014, followed by others like
Rucaparib,
Niraparib, and
Talazoparib. These drugs have shown efficacy in prolonging progression-free survival in patients, although they are not without side effects, including nausea, fatigue, and hematological toxicities.
Resistance to PARP Inhibitors
Despite their initial effectiveness, some cancers develop resistance to PARP inhibitors. Several mechanisms have been proposed for this resistance, including the restoration of homologous recombination through the reversion of BRCA mutations, increased drug efflux, and alterations in PARP enzyme expression. Understanding these mechanisms is critical for developing strategies to overcome resistance and improve patient outcomes.Combination Therapies Involving PARP Inhibitors
Researchers are actively exploring combination therapies to enhance the efficacy of PARP inhibitors. Combining PARP inhibitors with other treatments such as
chemotherapy,
radiotherapy, or immune checkpoint inhibitors is an area of intense investigation. These combinations aim to exploit different aspects of cancer cell biology to achieve better therapeutic outcomes.
Future Directions
The future of PARP inhibitors in cancer treatment looks promising, with ongoing research aimed at expanding their use beyond BRCA-mutated cancers. Studies are exploring the role of PARP inhibitors in other cancers with defects in DNA repair pathways, such as those involving
ATM or
ATR mutations. Additionally, the development of biomarkers to predict response to PARP inhibitors will be crucial for personalized medicine approaches.
