The discovery of synthetic lethality as a result of the combined loss of PARP1 and
BRCA has revolutionized the treatment of DNA repair-deficient cancers. With the development
of PARP inhibitors, patients displaying germline or somatic mutations in BRCA1 or
BRCA2 were presented with a novel therapeutic strategy. However, a large subset of
patients do not respond to PARP inhibitors. Furthermore, many of those who do respond
eventually acquire resistance. As such, combating de novo and acquired resistance
to PARP inhibitors remains an obstacle in achieving durable responses in patients.
In this review, we touch on some of the key mechanisms of PARP inhibitor resistance,
including restoration of homologous recombination, replication fork stabilization
and suppression of single-stranded DNA gap accumulation, as well as address novel
approaches for overcoming PARP inhibitor resistance.
