The
mammalian target of rapamycin (mTOR) is dysregulated in diverse
cancers and contributes to
tumor progression and drug resistance. The first generation of
mTOR inhibitors have failed to show clinical efficiency in treating
pancreatic cancers due in part to the feedback relief of the
insulin-like growth factor-1 receptor (IGF-1R)-AKT signaling pathway. The second generation of
mTOR inhibitors, such as
AZD8055, could inhibit AKT activation upon mTOR complex 2 (
mTORC2) inhibition. However, whether this generation of
mTOR inhibitors can obtain satisfactory activities in
pancreatic cancer therapy remains unclear. In this study, we found
AZD8055 did not show great improvement compared with
everolimus,
AZD8055 induced a temporal inhibition of AKT
kinase activities and AKT was then rephosphorylated. Additionally, we found that AZD8055-induced transient AKT inhibition increased the expression and activation of
epidermal growth factor receptor (EGFR) by releasing its transcriptional factors Fork-head box O 1/3a (FoxO1/3a), which might contribute to cell resistance to
AZD8055. The in vitro and in vivo experiments further indicated the combination of
AZD8055 and
erlotinib synergistically inhibited the
mTORC1/C2 signaling pathway, EGFR/AKT feedback activation, and cell growth, as well as suppressed the progression of
pancreatic cancer in a xenograft model. This study provides a rationale and strategy for overcoming
AZD8055 resistance by a combined treatment with the EGFR inhibitor
erlotinib in
pancreatic cancer therapy.