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Int. J. Mol. Sci. 2015, 16(2), 3267-3282; doi:10.3390/ijms16023267

mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer

1,†
,
1,†
,
2
,
1
,
1,* and 3,*
1
Department of Hepatobiliary and Pancreas Surgery, the First Hospital, Jilin University, Changchun 130021, China
2
Department of General Surgery, the Second Hospital of Jilin University, Changchun 130041, China
3
Genetic Engineering Laboratory of PLA, the Eleventh Institute of Academy of Military Medical Sciences of PLA, Changchun 130122, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Johannes Haybaeck
Received: 28 November 2014 / Revised: 13 January 2015 / Accepted: 27 January 2015 / Published: 3 February 2015
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
View Full-Text   |   Download PDF [5543 KB, uploaded 3 February 2015]   |  

Abstract

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. View Full-Text
Keywords: mTORC1/2 kinase; cell resistance; EGFR signaling; FoxO1/3a; feedback activation; pancreatic cancer mTORC1/2 kinase; cell resistance; EGFR signaling; FoxO1/3a; feedback activation; pancreatic cancer
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Wei, F.; Zhang, Y.; Geng, L.; Zhang, P.; Wang, G.; Liu, Y. mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer. Int. J. Mol. Sci. 2015, 16, 3267-3282.

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