Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Wei, Feng, Zhang, Yandong, Geng, Li, Zhang, Ping, Wang, Guangyi, Liu, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346894/
https://www.ncbi.nlm.nih.gov/pubmed/25654224
http://dx.doi.org/10.3390/ijms16023267
_version_ 1782359754642817024
author Wei, Feng
Zhang, Yandong
Geng, Li
Zhang, Ping
Wang, Guangyi
Liu, Yan
author_facet Wei, Feng
Zhang, Yandong
Geng, Li
Zhang, Ping
Wang, Guangyi
Liu, Yan
author_sort Wei, Feng
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4346894
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-43468942015-04-03 mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer Wei, Feng Zhang, Yandong Geng, Li Zhang, Ping Wang, Guangyi Liu, Yan Int J Mol Sci Article 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. MDPI 2015-02-03 /pmc/articles/PMC4346894/ /pubmed/25654224 http://dx.doi.org/10.3390/ijms16023267 Text en © 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wei, Feng
Zhang, Yandong
Geng, Li
Zhang, Ping
Wang, Guangyi
Liu, Yan
mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer
title mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer
title_full mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer
title_fullStr mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer
title_full_unstemmed mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer
title_short mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer
title_sort mtor inhibition induces egfr feedback activation in association with its resistance to human pancreatic cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346894/
https://www.ncbi.nlm.nih.gov/pubmed/25654224
http://dx.doi.org/10.3390/ijms16023267
work_keys_str_mv AT weifeng mtorinhibitioninducesegfrfeedbackactivationinassociationwithitsresistancetohumanpancreaticcancer
AT zhangyandong mtorinhibitioninducesegfrfeedbackactivationinassociationwithitsresistancetohumanpancreaticcancer
AT gengli mtorinhibitioninducesegfrfeedbackactivationinassociationwithitsresistancetohumanpancreaticcancer
AT zhangping mtorinhibitioninducesegfrfeedbackactivationinassociationwithitsresistancetohumanpancreaticcancer
AT wangguangyi mtorinhibitioninducesegfrfeedbackactivationinassociationwithitsresistancetohumanpancreaticcancer
AT liuyan mtorinhibitioninducesegfrfeedbackactivationinassociationwithitsresistancetohumanpancreaticcancer