Combining PARP Inhibition, Radiation, and Immunotherapy: A Possible Strategy to Improve the Treatment of Cancer?

Abstract

Immunotherapy has revolutionized the practice of oncology, improving survival in certain groups of patients with cancer. Immunotherapy can synergize with radiation therapy, increase locoregional control, and have abscopal effects. Combining it with other treatments, such as targeted therapies, is a promising means of improving the efficacy of immunotherapy. Because the value of immunotherapy is amplified with the expression of tumor antigens, coupling poly(ADP-ribose) polymerase (PARP) inhibitors and immunotherapy might be a promising treatment for cancer. Further, PARP inhibitors (PARPis) are being combined with radiation therapy to inhibit DNA repair functions, thus enhancing the effects of radiation; this association might interact with the antitumor immune response. Cytotoxic T lymphocytes are central to the antitumor immune response. PARP inhibitors and ionizing radiation can enhance the infiltration of cytotoxic T lymphocytes into the tumor bed, but they can also enhance PD-1/PDL-1 expression. Thus, the addition of immune checkpoint inhibitors with PARP inhibitors and/or ionizing radiation could counterbalance such immunosuppressive effects. With the present review article, we proposed to evaluate some of these associated therapies, and we explored the biological mechanisms and medical benefits of the potential combination of radiation therapy, immunotherapy, and PARP inhibitors.

Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation

“…Several PARP inhibitors are being evaluated in clinical trials [27], [28], [29]. The loss of DNA repair capacity in the presence of these inhibitors has led to their evaluation as single agents and as enhancers of cytotoxic agents that provoke DNA damage, such as alkylating agents and radiation therapy [30].…”

Quantification of cobimetinib, cabozantinib, dabrafenib, niraparib, olaparib, vemurafenib, regorafenib and its metabolite regorafenib M2 in human plasma by UPLC–MS/MS

“…Inhibiting PARP results in double‐strand DNA breaks which result in cell death (Ashworth, ). Although PARP inhibitors were initially intended for use in cancers driven by BRCA1 or 2 mutations, these drugs are now also being investigated for use in homologous repair‐deficient tumors lacking BRCA1 and 2 mutations and in combination with chemotherapy or radiation to enhance the DNA‐damaging effects (Cesaire et al, ; Lu, Liu, Pang, Pacak, & Yang, ).…”

First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor

“…4,5 Because many anticancer therapies act by inducing DNA damage in tumour cells, investigating the therapeutic potential of PARP inhibitors has generated considerable interest. 6,7 PARP inhibitors exert cytotoxic effects through the inhibition of the catalytic activity of PARP1/PARP2 by trapping PARP-DNA complexes, thereby preventing DNA replication and transcription. 8 Potent and specific inhibitors of PARP have been shown to sensitise cancer cells to the DNA-damaging effects of cytotoxic chemotherapy and radiotherapy.…”

“…4 , 5 Because many anticancer therapies act by inducing DNA damage in tumour cells, investigating the therapeutic potential of PARP inhibitors has generated considerable interest. 6 , 7 …”