PARP
Meaning of PARP: A family of DNA repair enzymes whose blockade kills cancer cells that have already lost their other way of mending breaks.
Definition of PARP
PARP stands for poly(ADP-ribose) polymerase, a family of enzymes that help cells repair damaged DNA. The best studied member detects a break in one strand of the double helix, attaches chains of a molecule called ADP-ribose to nearby proteins, and uses those chains as a beacon that summons the repair machinery to the exact site of the damage.
What does it repair?
Single-strand breaks, which occur constantly. Normal metabolism, ultraviolet light, radiation and several drugs all nick one strand of the double helix, and a cell sustains thousands of such events a day. The enzyme binds the break within seconds and recruits the repair proteins. Left unrepaired, a single-strand break becomes a far more dangerous double-strand break when the cell next copies its DNA and the copying machinery runs into it.
Why do drugs that block it work in cancer?
Because of an idea called synthetic lethality: two faults that are each survivable become fatal together. Cells with a faulty BRCA1 or BRCA2 gene have already lost the high-fidelity system for mending double-strand breaks. Blocking the enzyme means their single-strand breaks go unrepaired and convert into double-strand breaks they cannot fix, so they die. Healthy cells retain the BRCA route and survive the same drug, which is what gives the treatment its selectivity.
Where are PARP inhibitors used?
| Setting | Basis for use |
|---|---|
| Ovarian cancer | Maintenance after chemotherapy, particularly with a BRCA fault |
| Breast cancer | Advanced disease with an inherited BRCA fault |
| Prostate cancer | Disease carrying faults in DNA repair genes |
| Pancreatic cancer | Maintenance after platinum chemotherapy with a BRCA fault |
Several drugs of this kind are approved and in routine use, so a PARP inhibitor is an established treatment rather than an experimental one.
What are the limits?
Resistance develops, sometimes because a further mutation restores the BRCA repair function the drug was exploiting. Low blood counts, fatigue and nausea are the usual side effects, and rare marrow disorders have been reported with prolonged use. The drugs work only where the relevant repair defect exists, so genetic testing of the tumor or the patient guides their use, and much of the underlying research concerns PARP-1, the member of the family that does most of this work.
Also known as
Used in a sentence
Tumor testing showed a BRCA2 fault, and a PARP inhibitor was considered as maintenance treatment.
Good to know
PARP inhibitors are approved treatments rather than experimental ones, and their effect depends on the tumor carrying a separate defect in the repair pathway that mends double-strand breaks.