PARPi, BRCA, and gaps: controversies and future research

• Published in: Trends in cancer Vol. 10; no. 9; p. 857
• Main Authors: Dibitetto, Diego, Widmer, Carmen A, Rottenberg, Sven
• Format: Journal Article
• Language: English
• Published: United States 01.09.2024
• Subjects: Animals; BRCA1 Protein - genetics; BRCA2 Protein - genetics; DNA Breaks, Double-Stranded - drug effects; DNA Polymerase theta; DNA Repair - drug effects; DNA, Single-Stranded; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Homologous Recombination - drug effects; Humans; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Synthetic Lethal Mutations; BRCA; cancer; homologous recombination; gaps; DNA damage; PARP inhibitors
• DOI: 10.1016/j.trecan.2024.06.008

In recent years, various poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been approved for the treatment of several cancers to target the vulnerability of homologous recombination (HR) deficiency (e.g., due to BRCA1/2 dysfunction). In this review we analyze the ongoing debates and recent breakthroughs in the use of PARPis for BRCA1/2-deficient cancers, juxtaposing the 'double-strand break (DSB)' and 'single-stranded DNA (ssDNA) gap' models of synthetic lethality induced by PARPis. We spotlight the complexity of this interaction, highlighting emerging research on the role of DNA polymerase theta (POLθ) and ssDNA gaps in shaping therapy responses. We scrutinize the clinical ramifications of these findings, especially concerning PARPi efficacy and resistance mechanisms, underscoring the heterogeneity of BRCA-mutated tumors and the urgent need for advanced research to bridge the gap between laboratory models and patient outcomes.