Co-targeting PLK1 and mTOR induces synergistic inhibitory effects against esophageal squamous cell carcinoma.

Both polo-like kinase 1 (PLK1) and mammalian/mechanistic target of rapamycin (mTOR) are attractive therapeutic targets for cancer therapy. However, the efficacy of the combined inhibition of both pathways for treating esophageal squamous cell carcinoma (ESCC), an aggressive malignancy with poor prognosis, remains unknown. In this study, we found that suppression of PLK1 by specific siRNA or inhibitor attenuated mTOR activity in ESCC cells. Phosphorylated S6, a downstream effector of mTOR signaling, was significantly correlated with overexpression of PLK1 in a subset of ESCC. These data suggest that PLK1 activates mTOR signaling in vitro and in vivo. More importantly, the mTOR inhibitor rapamycin synergized with PLK1 inhibitor BI 2536 to inhibit ESCC cell proliferation in culture and in mice. Notably, combined treatment with BI 2536 and rapamycin produced more potent inhibitory effects on the activation of S6 and AKT than either alone. Further analysis reveals that PLK1 modulates both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) cascades. Therefore, dual inhibition of PLK1 and mTOR yields stronger antitumor effects, at least partially due to synergistic abrogated the activation of S6, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and AKT by cooperatively blocking mTORC1 and mTORC2 cascades. These results provide evidence that the mTOR inhibitor rapamycin synergistically enhances the antitumor effect of PLK1 inhibitor BI 2536 in ESCC cells. Simultaneous targeting of PLK1 and mTOR may thus be a novel and promising therapeutic strategy for ESCC.

KEY MESSAGES: PLK1 potentiates both mTORC1 and mTORC2 activities in ESCC cells. PLK1 expression positively correlated with mTOR activity in a subset of ESCC. Co-targeting of PLK1 and mTOR produced stronger antitumor effects partially due to synergistic inhibition of AKT, 4E-BP1 and S6 through cooperatively blocking mTORC2 and mTORC1 cascades. Combination targeting of PLK1 and mTOR may be a novel and promising therapeutic strategy for ESCC treatment.