Dysregulation of
mTORC1/
mTORC2 pathway is observed in many
cancers and
mTORC1 inhibitors have been used clinically in many
tumor types; however, the mechanism of
mTORC2 in
tumorigenesis is still obscure. Here, we mainly explored the potential role of
mTORC2 in
esophageal squamous cell carcinoma (ESCC) and its effects on the sensitivity of cells to
mTOR inhibitors. We demonstrated that RICTOR, the key factor of
mTORC2, and p-AKT (Ser473) were excessively activated in ESCC and their overexpression is related to
lymph node metastasis and the
tumor-node-
metastasis (TNM) phase of ESCC patients. Furthermore, we found that
mTORC1/
mTORC2 inhibitor
PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than
mTORC1 inhibitor
RAD001 due to RAD001-triggered feedback activation of AKT signal. Another, we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell cycle arrest and apoptosis. Noteworthy, knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling, and enhances inhibition efficacy of
PP242 on the phosphorylation of AKT and PRAS40, thus potentiates the antitumor effect of
RAD001 and
PP242 both in vitro and in vivo. Our findings highlight that selective targeting
mTORC2 could be a promising therapeutic strategy for future treatment of ESCC.