DNA Repair and PARP
Cells in the human body are under constant attack from environmental factors that can cause damage to the DNA. There are various types of DNA damage, and cells have a number of different mechanisms for repairing DNA damage. Tumor cells that are deficient in homologous recombination (HR) because of defects in genes such as BRCA1 and BRCA2 can still repair DNA through base excision repair (BER). PARP proteins play an important role in the BER process. Preventing BER through PARP inhibition in HR-deficient cells induces cell death through a mechanism known as synthetic lethality. Synthetic lethality only occurs in the tumor cells that have the HR deficiency and not in normal cells. Thus, blocking PARP activity with rucaparib may be beneficial in ovarian cancer patients who have BRCA mutations, as well as other defects in DNA repair in their tumor cells.
Clovis is working with a Foundation Medicine to develop a companion diagnostic for rucaparib. The goal of the collaboration is to develop a DNA sequencing tumor tissue test to select cancer patients most likely to respond to rucaparib. As a first step in this process an experimental biomarker test will be used in ARIEL studies.