Preclinical evaluation of the dual mTORC1/2 inhibitor sapanisertib in combination with cisplatin in nasopharyngeal carcinoma.

A wide range of investigational drugs are being investigated in clinical trials for the treatment of nasopharyngeal carcinoma (NPC), including PI3K-mTOR inhibitor. The purpose of this study was to evaluate the effective combination of TORC1/2 inhibitor sapanisertib and chemotherapy drug cisplatin in preclinical models of NPC. In our work, sapanisertib at nanomolar concentrations decreases viability and proliferation in NPC cells regardless of varying genetic backgrounds. Sapanisertib acts synergistically with cisplatin via induces more G0/G1 arrest and apoptosis. At the same concentration, sapanisertib neither decreases viability nor proliferation in normal nasal epithelial cells. Sapanisertib also decreases NPC cell migration. It decreases phosphorylation of Akt, mTOR, p70S6K and 4EBP1 in NPC cells. The in vitro findings on the inhibitory effects of sapanisertib on NPC growth and mTOR signaling were also evident in the NPC xenograft mouse model. In addition, combination of sapanisertib with cisplatin resulted in better efficacy than monotherapy to inhibit NPC growth in mice without causing significant toxicity. These data clearly demonstrate efficacy and insignificant toxicity of sapanisertib alone and its combination with cisplatin in NPC preclinical models. Our findings will accelerate clinical trials evaluating combination of sapanisertib and chemotherapy for NPC treatment.
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