88P - Impact of poly(ADP-ribose) polymerase (PARP) mutations on interaction with PARP inhibitors (iPARPs)

Background

Poly(ADP-ribose) polymerase (PARP) plays a crucial role in DNA repair pathways. PARP trapping induced by PARP inhibitors (iPARPs) leads to replication fork collapse, resulting in clinically relevant cytotoxicity. Therefore, the aim of this study is to describe the potential impact of PARP mutations on interaction with iPARPs.

Methods

The study design involved molecular docking simulations between iPARPs (olaparib, rucaparib, and niraparib) and PARP using Autodock Vina. We reviewed PARP mutations in the COSMIC database and predicted the pathogenicity of mutations near the interaction residues of PARP with the identified iPARPs from the molecular docking.

Results

The amino acids may be related to the interaction of olaparib (Lysine703, Arginine704, Glutamate642, Leucine641, Alanine555, Tryptophan626), niraparib (Alanine555, Tryptophan626, Lysine551, Valine552, Serine554, Glycine530), and rucaparib (Arg878, Aspartate770, Aspartate766, Glutamine759, Glycine888, Tyrosine907) with PARP. In the database, 867 mutations for PARP1 are reported. Among the amino acid residues identified for interaction with olaparib, only the mutation at amino acid 555 (Alanine555Valine) was reported. Regarding niraparib binding sites, mutations were found in amino acids 551 (Lysine551Arginine) and 626 (Tryptophan626Leucine). For Rucaparib, mutations were identified in amino acids 759 (Glutamine759Proline), 766 (Aspartic Acid766Asparagine), 878 (Arginine878Tryptophan), and 888 (Glycine888Aspartic Acid).

Conclusions

Amino acids and their mutations that could be involved in the interaction of olaparib, rucaparib, and niraparib with PARP were identified. Recognizing fewer mutations interacting with olaparib and a greater number interacting with the other PARP inhibitors, olaparib has demonstrated superiority in patients with recurrent disease and BRCA mutations sensitive to platinum. However, prospective studies comparing different PARP inhibitors are needed. Our findings highlight the importance of PARP1 interaction with inhibitors in conferring intrinsic resistance with this new therapy. Further study and supplementation of PARP1 mutation databases are necessary to understand their impact on functionality and determine clinical implications.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

J.F. Diaz Acosta.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.