PARP inhibitors are a class of targeted therapy drugs used in cancer treatment. These medications are designed to interfere with specific processes within cancer cells, aiming to selectively destroy them or prevent their growth.
The Body’s DNA Repair System
DNA, the genetic material within our cells, is constantly exposed to factors that can cause damage, both from normal cellular processes and external sources like UV radiation or chemicals. Maintaining the integrity of DNA is important for proper cell function and overall organism survival. If DNA damage goes unrepaired, it can lead to harmful mutations, cell dysfunction, or even cell death.
Cells possess various DNA repair mechanisms to counteract this constant threat. These systems are specialized to address different types of damage, such as single-strand breaks or more severe double-strand breaks. Pathways like base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), and non-homologous end joining (NHEJ) collectively ensure genetic stability.
The PARP Enzyme’s Role
The Poly (ADP-ribose) polymerase (PARP) enzyme, particularly PARP1, plays a significant role in the cell’s DNA repair machinery. It acts as a DNA damage sensor, detecting and binding to sites of DNA lesions, especially single-strand breaks. Once PARP1 binds to damaged DNA, its structure changes, activating its enzymatic activity.
This activation leads to PARylation, where PARP1 synthesizes and attaches poly(ADP-ribose) (PAR) chains to itself and other target proteins. These PAR chains recruit other DNA repair proteins to the site of damage. This recruitment facilitates the repair of single-strand breaks, primarily through the base excision repair (BER) pathway.
How PARP Inhibitors Work
PARP inhibitors interfere with the PARP enzyme’s function through two main mechanisms: catalytic inhibition and PARP trapping. Catalytic inhibition involves the PARP inhibitor binding to the catalytic site of the PARP enzyme. This competitive binding prevents PARP from performing PARylation, thereby hindering its ability to recruit repair proteins and effectively repair single-strand breaks. As a result, these unrepaired single-strand breaks can accumulate.
The second mechanism is PARP trapping. When a PARP inhibitor is present, it can “trap” the PARP enzyme on the DNA at the site of damage. While PARP normally binds to DNA damage and then dissociates after initiating repair, PARP inhibitors prevent this dissociation, leaving the enzyme tightly bound to the DNA. This trapped PARP-DNA complex creates a cytotoxic lesion that is more difficult for the cell to repair.
The combined effect of catalytic inhibition and PARP trapping leads to the concept of “synthetic lethality.” In normal cells, if one DNA repair pathway is compromised, other pathways can compensate, allowing the cell to survive. However, in cancer cells that already have defects in other DNA repair pathways, particularly homologous recombination (HR), inhibiting PARP becomes lethal.
For instance, cells with mutations in BRCA1 or BRCA2 genes have a compromised HR pathway, which is responsible for repairing double-strand breaks. When PARP is inhibited in these cells, the unrepaired single-strand breaks convert into double-strand breaks during DNA replication. Since the HR pathway is already deficient, the cancer cells cannot repair these accumulating double-strand breaks, leading to genomic instability and ultimately cell death, while healthy cells with intact HR can still repair the damage.
Clinical Applications
The mechanism of action of PARP inhibitors makes them effective for treating certain cancers, especially those with DNA repair deficiencies. These drugs are effective for cancers that harbor mutations in genes like BRCA1 and BRCA2, or other homologous recombination deficiency (HRD) markers. Such genetic alterations impair the cell’s ability to repair DNA double-strand breaks, creating a vulnerability that PARP inhibitors can exploit.
PARP inhibitors are used in the treatment of ovarian, breast, and prostate cancers, with ongoing clinical trials exploring their efficacy in other tumor types. For example, olaparib was initially approved for advanced ovarian cancer patients with BRCA mutations and has since shown benefits in other BRCA-mutated cancers. The use of these drugs has expanded to include patients without BRCA mutations but with other HRD indications.