Targeting the PARP pathway has been successfully exploited as a new therapeutic approach in a number of cancers [1]. Effective PARP inhibitors trap PARP on DNA and prevent the cellular DNA repair machinery from working [1, 2]. The Figure below details the steps when a PARP inhibitor is present:
Step 1: Following detection of a DNA lesion, normally PARP1 is autoPARylated and recruits DNA repair proteins.
Step 2: However, treatment with PARP inhibitors blocks PARP autoPARylation, and prevents recruitment of other DDR proteins.
Step 3: More importantly, PARP1 becomes trapped on the damaged DNA, resulting in the ‘zip’ of the DNA replication machinery crashing into the trapped PARP, and leading to collapse of the replication fork and formation of a double strand break in the DNA.
Figure 2: PARP inhibition traps the PARP molecule on the DNA, ultimately leading to cell death
Adapted from Gourley, et al., J Clin Oncol 2019
PARP inhibitors act by trapping PARP on DNA, which is key as it presents a physical obstacle to the replication machinery. To resolve the PARP-DNA interaction, HRR is necessary. Therefore, in HRR-deficient cancer cells, trapped PARP results in replication fork collapse and finally cell death.
Importantly, HRR is required to accurately repair the resulting double-strand breaks. In cells that are HRR deficient, for example due to loss of BRCA1/2, double-strand break repair is imprecise and leads to DNA damage accumulation, which leads to cell death [3]. Identifying patients who are likely to respond to PARP inhibitors due to HRR deficiency in their tumours can increase response rates to therapy. [1]
At present, four PARP1/2 inhibitors (olaparib, rucaparib, niraparib and talazoparib) have received marketing authorisation in Europe and/or the United States [4-9].
References
- Gourley C, Balmana J, Ledermann JA et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019; doi: 10.1200/JCO.1218.02050. [Epub ahead of print].
- Murai J, Huang SY, Das BB et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 2012; 72: 5588-5599.
- Moynahan ME, Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 2010; 11: 196-207.
- AstraZeneca. LYNPARZA® (olaparib) tablets for oral use. 2018.
- European Medicines Agency. Olaparib Summary of Product Characteristics. 2019.
- Clovis Oncology. RUBRACA® (rucaparib) tablets, for oral use. 2018.
- European Medicines Agency. Rucaparib Summary of Product Characteristics. 2018
- Tesaro. ZEJULA® (niraparib) capsules, for oral use [prescribing information].2018.
- Pfizer. TALZENNA™ (talazoparib) capsules, for oral use [prescribing information]. New York, NY: Pfizer Inc,2018.