Poly (ADP-ribose) polymerases, known as PARPs, are proteins found naturally within our cells. These enzymes play a significant role in maintaining the integrity of our genetic material. Their involvement in DNA repair pathways makes them relevant in the study and treatment of diseases, including cancer. This class of proteins has gained attention as a therapeutic target.
Understanding PARP Enzymes and Their Function
PARP enzymes, particularly PARP1 and PARP2, are central to the body’s DNA repair machinery. Their main job is to detect and respond to DNA damage, specifically single-strand breaks. When a break occurs in one of the DNA strands, PARP1 quickly binds to the damaged site. This binding activates PARP1, which then catalyzes a process called poly-ADP-ribosylation, adding chains of ADP-ribose to itself and other repair proteins.
This modification acts as a signal, recruiting other DNA repair proteins to the site of the break. The assembly of these proteins forms a complex that mends the DNA, ensuring the genetic code remains accurate. This repair mechanism, known as base excision repair (BER), helps maintain genomic stability and prevent mutations that could lead to disease. Without functional PARP enzymes, even minor DNA damage could accumulate, compromising cell health.
How PARP Inhibitors Target Cancer
PARP inhibitors are drugs designed to block the activity of PARP enzymes. When these inhibitors bind to PARP, they prevent the enzyme from carrying out its DNA repair functions, specifically the repair of single-strand breaks. This blockade leads to an accumulation of unrepaired single-strand breaks. During DNA replication, these single-strand breaks can transform into more severe double-strand breaks.
Cancer cells often have existing defects in other DNA repair pathways, such as homologous recombination, which is responsible for repairing double-strand breaks. This deficiency is common in cancers with BRCA1 or BRCA2 mutations. When PARP inhibitors prevent single-strand break repair, and the cancer cell cannot repair the resulting double-strand breaks due to a pre-existing defect, the damage becomes overwhelming. This leads to a concept known as “synthetic lethality,” where the combination of two non-lethal events (PARP inhibition and a homologous recombination defect) becomes lethal to the cancer cell. Extensive, unrepaired DNA damage ultimately triggers programmed cell death in cancer cells, while healthy cells with intact homologous recombination pathways can cope.
Cancers Treated with PARP Inhibitors
PARP inhibitors are used to treat several types of cancer, particularly those with underlying DNA repair deficiencies. They are approved for ovarian cancer, especially when cancer cells have BRCA1 or BRCA2 mutations. These mutations impair the homologous recombination pathway, making the cancer cells highly susceptible to PARP inhibition.
Beyond ovarian cancer, PARP inhibitors have also shown effectiveness in certain types of breast cancer, particularly those that are BRCA-mutated and HER2-negative. They are also used in metastatic prostate and pancreatic cancer, especially when these cancers harbor BRCA mutations or other DNA repair defects. Their effectiveness stems from synthetic lethality, exploiting the cancer cell’s existing DNA repair vulnerabilities.
Potential Side Effects of PARP Inhibitors
While PARP inhibitors offer targeted treatment for certain cancers, they can cause various side effects. Common side effects include fatigue, nausea, vomiting, or a decrease in appetite.
Blood-related side effects, such as anemia (low red blood cell count), thrombocytopenia (low platelet count), and neutropenia (low white blood cell count), collectively fall under myelosuppression. These effects are managed by healthcare professionals through dose adjustments or supportive care. The specific side effects and their severity vary among individuals and depend on the particular PARP inhibitor used.