The potential of PARP inhibitors in targeted cancer therapy and immunotherapy

Abstract

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.

Investigating Protein Binding with the Isothermal Ligand‐induced Resolubilization Assay

“…Human PARP1 is a multi‐domain, 113‐kDa protein that transfers ADP ribosyl groups from NAD + to acceptor chromatin and chromatin‐associated proteins, and mediates base excision repair in DNA single‐strand breaks [35] . Given its role in DNA repair processes, PARP1 is an attractive target as part of combination therapy for many cancers [36] . For the purpose of this proof‐of‐concept study, only its 39.6‐kDa catalytic domain was used to test Olaparib response in ILIRA.…”

“…[35] Given its role in DNA repair processes, PARP1 is an attractive target as part of combination therapy for many cancers. [36] For the purpose of this proof-of-concept study, only its 39.6-kDa catalytic domain was used to test Olaparib response in ILIRA. Olaparib is a small molecule PARP1 inhibitor with a reported IC 50 of 5 nM that competes against NAD + for binding in the catalytic domain.…”

Personalized treatment with PARP inhibitors in advanced urothelial carcinoma: a case report and literature review

“…These trials are categorized based on the different FDA-approved PARP inhibitors, encompassing olaparib, rucaparib, niraparib, and talazoparib. 12 Some studies suggest talazoparib may exhibit superiority over olaparib against BC cells. 14 …”

“…While the use of PARP inhibitors has been validated for ovarian, breast, pancreatic, and recently prostate cancers, 12 their application in BC is not yet approved. This highlights a potential avenue for therapeutic intervention given the significant role of DDR in BC.…”

Comparison of mutation landscapes of pretreatment versus recurrent squamous cell carcinoma of the oral cavity: The possible mechanism of resistance to standard treatment

“… 47 This may explain the typically good responses to DNA damage‐induced first‐line therapies in this disease. It is also interesting to see, whether PARP inhibitors, such as olaparib and rucaparib, which are currently used in ovarian and breast cancer with DNA repair defects, 48 may be also used in OSCC containing mutations of DNA repair genes. From these data, it appears to be a plausible conclusion that the use of data on DNA repair gene mutations may help to guide treatment plans for primary OSCC as well as the follow‐up after the completion of each treatment.…”