The potential of PARP inhibitors in targeted cancer therapy and immunotherapy.
BRCA
DNA repair
PARP inhibitors
cancer
immune checkpoint inhibitors
immunotherapy
synthetic lethality
Journal
Frontiers in molecular biosciences
ISSN: 2296-889X
Titre abrégé: Front Mol Biosci
Pays: Switzerland
ID NLM: 101653173
Informations de publication
Date de publication:
2022
2022
Historique:
received:
18
10
2022
accepted:
15
11
2022
entrez:
19
12
2022
pubmed:
20
12
2022
medline:
20
12
2022
Statut:
epublish
Résumé
DNA damage response (DDR) deficiencies result in genome instability, which is one of the hallmarks of cancer. Poly (ADP-ribose) polymerase (PARP) enzymes take part in various DDR pathways, determining cell fate in the wake of DNA damage. PARPs are readily druggable and PARP inhibitors (PARPi) against the main DDR-associated PARPs, PARP1 and PARP2, are currently approved for the treatment of a range of tumor types. Inhibition of efficient PARP1/2-dependent DDR is fatal for tumor cells with homologous recombination deficiencies (HRD), especially defects in breast cancer type 1 susceptibility protein 1 or 2 (BRCA1/2)-dependent pathway, while allowing healthy cells to survive. Moreover, PARPi indirectly influence the tumor microenvironment by increasing genomic instability, immune pathway activation and PD-L1 expression on cancer cells. For this reason, PARPi might enhance sensitivity to immune checkpoint inhibitors (ICIs), such as anti-PD-(L)1 or anti-CTLA4, providing a rationale for PARPi-ICI combination therapies. In this review, we discuss the complex background of the different roles of PARP1/2 in the cell and summarize the basics of how PARPi work from bench to bedside. Furthermore, we detail the early data of ongoing clinical trials indicating the synergistic effect of PARPi and ICIs. We also introduce the diagnostic tools for therapy development and discuss the future perspectives and limitations of this approach.
Identifiants
pubmed: 36533080
doi: 10.3389/fmolb.2022.1073797
pii: 1073797
pmc: PMC9751342
doi:
Types de publication
Journal Article
Review
Langues
eng
Pagination
1073797Informations de copyright
Copyright © 2022 Hunia, Gawalski, Szredzka, Suskiewicz and Nowis.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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