Olaparib enhancing radiosensitization and anti-metastatic effect of oral cancer by targeting IL-17A signal.

Abstract

We tested whether the PARP inhibitor, Olaparib, can effectively enhance radiosensitivity while inhibiting OSCC growth and metastasis in vitro and in vivo. Patient samples were used for survival validation. The present study investigated the effect of Olaparib and ionizing radiation (IR) on clonogenic, migratory, and invasive ability in human IR-sensitive (OML1) and IR-resistant (OML1-R) OSCC cell lines. We next explored the underlying mechanism with ELISA and a Western blotting assay. Two in vivo mouse models were established to investigate the efficacy of Olaparib combined with radiotherapy (RT) on local tumor growth and lung metastasis. IL-17A expression was confirmed in tissue specimens of OSCC patients by immunohistochemistry. We found that Olaparib, in combination with IR, substantially inhibited cell growth, migration, and invasion in vitro. Mechanistically, the Olaparib treatment significantly reduced the secretion of IL-17A in irradiated OSCC cells by attenuating NF-κB and p38 activity. Consistently, Olaparib enhanced the radiosensitivity and, with RT, synergistically reduced both tumor growth and lung metastasis in mice. In addition, OSCC patients with high IL-17A expression were substantially associated with an increased risk of lymph node involvement and worse survival. This study has highlighted that Olaparib displays radiosensitizing and antimetastatic effects by inhibiting the IL-17A-dependent signal. Remarkably, Olaparib could provide a remarkable anticancer efficacy to improve treatment response in OSCC patients with recurrent/metastatic disease after RT.