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PARP inhibitors represent the first DDR therapeutic “blockbusters” with multiple FDA-approved products expected to exceed $1B in annual sales.

PARP is a key enzyme involved in sensing and repairing DNA single-strand breaks (SSBs). If SSBs are left unrepaired, the devolve into double-strand breaks (DSBs), which are lethal to the cancer cell. PARP-inhibitors prevent PARP from repairing SSBs, leading to increased DSBs. Cancer cells that are deficient in DSB repair, such as those with BRCA mutations, will be killed indirectly by blocking PARP in a process known as “synthetic lethality”1

1 O’Neil, Nature Reviews (2017) Diagrams adapted from Benke, Fronters in Genetics (2012) and Zheng, Biomedicine & Pharmacotherapy (2020)