Targeting the PI3K/AKT/mTOR signaling pathway as an effectively radiosensitizing strategy for treating human oral squamous cell carcinoma in vitro and in vivo.

Radiation therapy (RT) is the current standard adjuvant approach for oral squamous cell carcinoma (OSCC) patients. Radioresistance is a major contributor to radiotherapy failure. In this study, we used patient-derived cells and a radiation-resistant cell line in vitro and in vivo for two purposes: evaluate the anti-tumor effects and understand the mechanisms in the dual PI3K/mTOR signaling pathway regulation of radiosensitization. Our findings indicate that in OML1-R cells, the radioresistance phenotype is associated with activation of the PI3K/AKT/mTOR signaling pathway. Compared to a combination of PI3K or mTOR inhibitors and radiation, dual blockade of the PI3K and mTOR kinases significantly improved radiation efficacy in oral cancer and patient-derived OSCC cells. Dual PI3K/mTOR inhibition enhanced the effect of radiation by inhibiting AKT/mTOR signaling pathways and caused G1 phase arrest, which is associated with downregulation of cyclin D1/CDK4 activity, leading to growth inhibition. In nude mice xenografted with radioresistant OML1-R cells, the combined treatment was also more effective than RT alone in reducing tumor growth. This treatment was also demonstrated to be dependent on the inhibition of protein kinase-dependent S6 kinase pathway and eIF4E-mediated cap-dependent translation. These findings indicate that activation of the PI3K/AKT/mTOR signaling pathway has a role in radioresistance of OSCC. We determined that a PI3K/mTOR inhibitor combined with radiation exhibits synergistic inhibition of the AKT/mTOR axis and induces cell cycle arrest. Our results show the therapeutic potential of drugs targeting the PI3K/AKT/mTOR signaling pathway should be new candidate drugs for radiosensitization in radiotherapy.