Poly (ADP-ribose) polymerase or PARP proteins are a family of enzymes found within cells that play important roles in DNA repair. There are around 17 different PARP protein members that have been identified, with PARP1 and PARP2 being the most studied. In normal cells, PARP proteins work to detect and signal DNA damage, which then recruits DNA repair proteins to the site of breaks to facilitate repair. However, in cancer cells that have DNA repair defects, inhibiting PARP can prevent damaged DNA from being repaired, ultimately leading to cancer cell death.

Mechanism of action

Poly (ADP-ribose) polymerase or Polymerase inhibitors work by binding to the active site of PARP enzymes, mainly PARP1 and PARP2, which prevents them from functioning properly. When PARP is inhibited, single-stranded DNA breaks are left unrepaired and are then converted into double-stranded breaks during DNA replication. Double-stranded breaks are much harder for cancer cells to repair if they have certain DNA repair defects, most notably in homologous recombination repair (HRR) genes like BRCA1 and BRCA2. This leads to genomic instability and cancer cell death through a process known as synthetic lethality. Polymerase inhibitors essentially exploit DNA repair deficiencies in cancer cells.

Targeting BRCA mutant cancers

One of the biggest successes for PARP Inhibitors has been in treating cancers with mutations in BRCA1 and BRCA2 genes. BRCA1 and BRCA2 normally help repair DNA damage through the HRR pathway. However, when mutated they no longer function correctly, leaving cells with impaired HRR. Polymerase inhibitors are able to selectively kill these BRCA mutant cancer cells by preventing DNA repair through other pathways like base excision repair. A number of Polymerase inhibitors have shown activity against BRCA mutant breast, ovarian and prostate cancers in clinical trials and some have been approved by the FDA.

Going beyond BRCA mutations

Researchers have also started to explore other DNA repair defects that could make cancers susceptible to PARP inhibition through the same concept of synthetic lethality. For example, mutations in other HRR genes beyond BRCA1/2 like ATM, ATR, FANC and PALB2 have shown promise as predictive biomarkers. Epigenetic silencing of BRCA1 through promoter methylation is another situation where Polymerase inhibitors may be useful. Polymerase inhibitors are also being studied in combination with other DNA damaging agents like chemo and radiotherapy to enhance their effects. This type of combination treatment aims to expand the use of Polymerase inhibitors to broader patient populations.

Clinical testing of newer Parp Inhibitor

A handful of Polymerase inhibitors have been approved or are in late stage clinical testing for different cancer types. Talazoparib was the first approved specifically for germline BRCA mutated HER2-negative breast cancer in 2018. Olaparib gained broader approval in 2020 for BRCA mutated metastatic pancreatic cancer. Niraparib is approved for recurrent ovarian cancer regardless of BRCA status. Rucaparib was approved for recurrent ovarian cancer with BRCA mutations and later expanded to all homologous recombination deficiency mutations. Veliparib and cediranib are still in ongoing clinical trials. Research continues to better understand biomarkers of response to help guide patient selection and maximize the benefits of these promising targeted therapies.

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