PARP
PARP is a DNA repair enzyme. Cancers that have already lost one repair system (BRCA) die when this second one is blocked; healthy cells survive.
PARP inhibitors (olaparib, niraparib, rucaparib, talazoparib) exploit synthetic lethality with BRCA1/2 mutations and homologous recombination deficiency in ovarian, breast, prostate, and pancreatic cancer. Olaparib is approved in adjuvant germline-BRCA breast cancer (OlympiA). PARP1-selective inhibitors (saruparib) and PARP PET tracers are the next step.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · PARP is a DNA repair enzyme. Cancers that have already lost one repair system (BRCA) die when this second one is blocked; healthy cells survive.
- 1 · What it is
PARP is a DNA repair enzyme. Cancers that have already lost one repair system (BRCA) die when this second one is blocked; healthy cells survive.
- 2 · What goes wrong in cancer
Poly(ADP-ribose) polymerase 1 senses single-strand breaks; trapping on DNA is the key cytotoxic mechanism.
- 3 · How drugs use it
5 products aim at PARP: small molecules. Inhibitors are shaped to fit the enzyme's active site so the reaction the cancer relies on stops.
Biology
Poly(ADP-ribose) polymerase 1 senses single-strand breaks; trapping on DNA is the key cytotoxic mechanism.
- BRCA/HRD ovarian, breast, prostate, pancreatic cancers
How common it is, by cancer
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Ovarian cancer | 50% | HRD-positive (BRCA or genomic scar) | ~20% germline/somatic BRCA | Wikipedia |
| Prostate cancer | 20-25% | HRR gene alteration (mCRPC) | BRCA2 ~8-10% | cBioPortal (TCGA) |
| Triple-negative breast cancer | 15-20% | Germline BRCA1/2 | ~40-50% HRD by scar | Wikipedia |
| Pancreatic ductal adenocarcinoma | 5-8% | Germline BRCA1/2 or PALB2 | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Billed as the first PARP inhibitor for triple-negative breast cancer, it failed its phase 3 in 2011. It turned out not to inhibit PARP at all.
Niraparib is a PARP inhibitor approved as maintenance for ovarian cancer regardless of BRCA status, and in prostate cancer with abiraterone.
Olaparib was the first PARP inhibitor, and turned an inherited BRCA mutation from a risk factor into a drug target, including after surgery in breast cancer.
A PARP inhibitor for BRCA-mutated ovarian and prostate cancer whose original maker went bankrupt; still available, with a narrowed label.
Talazoparib is the most potent PARP trapper, approved in BRCA breast cancer and with enzalutamide in prostate cancer.
Everyone with HER2-negative early breast cancer that meets high-risk criteria should be offered germline BRCA testing, because a positive result now changes treatment: a year of olaparib after chemotherapy reduces relapse and death. It does not apply to low-risk tumours, HER2-positive disease, or somatic-only BRCA mutations.
Women with newly diagnosed advanced ovarian cancer should have their tumour tested for BRCA mutations and homologous recombination deficiency, because those who are HRD-positive gain years of additional disease control and better survival from adding olaparib to bevacizumab maintenance. Those who are HRD-negative gain nothing from olaparib in this combination and should not be exposed to its toxicity and cost. HRD testing has become a routine part of ovarian cancer care as a result.
Every woman diagnosed with advanced high-grade ovarian cancer should be tested for BRCA mutations at diagnosis, because those who carry one should receive two years of olaparib after chemotherapy, which greatly extends the time in remission and improves long-term survival. The plateau in the survival curves suggests some patients are cured by this approach. Toxicity is mostly anaemia, fatigue and nausea, and the two-year limit appears sufficient.
Latest papers
topQuery for this target: (TITLE:"PARP" OR ABSTRACT:"PARP" OR TITLE:"PARP1" OR ABSTRACT:"PARP1") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about PARP, not a curated reading list.
Pages like this
not linked directly; found by shared links- TargetBRCA1 / BRCA2 (HRD)
- TermSynthetic lethality
Shares Christopher Lord, A synthetic lethality map for every cancer driver in every tissue context, Newcastle Cancer Centre / Northern Centre for Cancer Care, Tumour suppressor gene.
- TargetATR
Shares Subtype-directed therapy for SCLC (ASCL1 / NEUROD1 / POU2F3 / inflamed), Radioligand plus DNA-repair inhibitor combinations, Enabling characteristic: genome instability and mutation, Base excision repair, PARP & alkylation damage.
- IdeactDNA-guided duration of PARP maintenance
Shares PRIMA / ENGOT-OV26, SOLO-1, Niraparib, PARP inhibitors.
- InstitutionARCAGY-GINECO
Shares PAOLA-1 / ENGOT-ov25, HRD & BRCA testing, Niraparib, Homologous recombination deficiency (HRD).
- PairingPARP inhibitor + AR pathway inhibitor (prostate)
Shares Niraparib, Talazoparib, Androgen receptor signalling, DNA damage response & homologous recombination.
- CompanyAstraZeneca
Shares Sheba Medical Center, SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer, PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours, OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer.
- TargetWEE1
Shares DNA replication stress, DNA damage response & homologous recombination, Synthetic lethality: paired dependencies, Double-strand break repair: HR versus end joining.