PARP inhibitors

Poly(ADP-ribose) polymerase inhibitors, commonly known as PARP inhibitors, are a class of pharmacological inhibitors that have a targeted action on one or more of the poly(ADP-ribose) polymerase (PARP) enzymes. These enzymes are involved in several important cellular processes, including DNA repair, genomic stability, and programmed cell death. By inhibiting PARP, these drugs are particularly effective in treating cancers that have defects in their DNA repair mechanisms, such as BRCA1 and BRCA2 mutations in breast and ovarian cancers.

Mechanism of Action

PARP inhibitors work by blocking the action of PARP enzymes, which play a key role in repairing damaged DNA. When PARP enzymes are inhibited, single-strand breaks in DNA cannot be repaired, leading to the accumulation of DNA damage. In cells with existing defects in the DNA repair pathways, such as those with BRCA mutations, this results in double-strand breaks that the cell cannot repair, ultimately leading to cell death. This mechanism is referred to as "synthetic lethality."

Clinical Applications

PARP inhibitors have shown significant promise in the treatment of several types of cancer, particularly:

• Ovarian cancer: They are approved for the treatment of advanced ovarian cancer, especially in patients with BRCA mutations.
• Breast cancer: Certain PARP inhibitors are approved for treating HER2-negative metastatic breast cancer with a germline BRCA mutation.
• Prostate cancer and Pancreatic cancer: Research and clinical trials are ongoing to evaluate the efficacy of PARP inhibitors in these and other types of cancer.

Approved PARP Inhibitors

Several PARP inhibitors have been approved by regulatory agencies such as the FDA for clinical use, including:

• Olaparib (Lynparza)
• Rucaparib (Rubraca)
• Niraparib (Zejula)
• Talazoparib (Talzenna)

Each of these drugs has a specific set of indications and is chosen based on the patient's genetic makeup and the type of cancer being treated.

Side Effects

While PARP inhibitors offer a targeted approach to cancer treatment, they can also cause side effects, including:

• Nausea and vomiting
• Fatigue
• Anemia
• Risk of developing myelodysplastic syndrome or acute myeloid leukemia
• Gastrointestinal issues

Future Directions

Research is ongoing to expand the use of PARP inhibitors beyond BRCA-mutated cancers, explore their potential in combination therapies, and understand mechanisms of resistance. The development of biomarkers to predict response to PARP inhibitors is also an area of active investigation.

See Also

• DNA repair
• BRCA1
• BRCA2
• Synthetic lethality
• Cancer therapy

‎