Insights into the Possible Molecular Mechanisms of Resistance to PARP Inhibitors

Simple Summary The increasingly wide use of PARP inhibitors in breast, ovarian, pancreatic, and prostate cancers harbouring a pathogenic variant in BRCA1 or BRCA2 has highlighted the problem of resistance to therapy. This review summarises the complex interactions between PARP1, cell cycle regulation, response to stress replication, homologous recombination, and other DNA damage repair pathways in the setting of BRCA1/2 mutated cancers that could explain the development of primary or secondary resistance to PARP inhibitors. PARP1 enzyme plays an important role in DNA damage recognition and signalling. PARP inhibitors are approved in breast, ovarian, pancreatic, and prostate cancers harbouring a pathogenic variant in BRCA1 or BRCA2, where PARP1 inhibition results mainly in synthetic lethality in cells with impaired homologous recombination. However, the increasingly wide use of PARP inhibitors in clinical practice has highlighted the problem of resistance to therapy. Several different mechanisms of resistance have been proposed, although only the acquisition of secondary mutations in BRCA1/2 has been clinically proved. The aim of this review is to outline the key molecular findings that could explain the development of primary or secondary resistance to PARP inhibitors, analysing the complex interactions between PARP1, cell cycle regulation, PI3K/AKT signalling, response to stress replication, homologous recombination, and other DNA damage repair pathways in the setting of BRCA1/2 mutated cancers.

Automated summary

The role of the PARP1 enzyme in recognizing and signaling DNA damage is important. PARP inhibitors are primarily used to treat breast, ovarian, pancreatic, and prostate cancers with BRCA1 or BRCA2 pathogenic variants, but their widespread use has raised the issue of therapy resistance. This review summarizes key molecular findings that could explain the development of primary or secondary resistance to PARP inhibitors.