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

Author： Wei Feng   Zhang Yandong   Geng Li   Zhang Ping   Wang Guangyi   Liu Yan  

Publisher： MDPI

E-ISSN： 1422-0067|16|2|3267-3282

ISSN： 1422-0067

Source： International Journal of Molecular Sciences, Vol.16, Iss.2, 2015-02, pp. : 3267-3282

Access to resources Favorite

Disclaimer: Any content in publications that violate the sovereignty, the constitution or regulations of the PRC is not accepted or approved by CNPIEC.

Previous Menu Next

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.

Related content

The mTOR Signalling Pathway in Human Cancer

By Pópulo Helena   Lopes José Manuel   Soares Paula  

International Journal of Molecular Sciences, Vol. 13, Iss. 2, 2012-02 ,pp. : 1886-1918 (33)

MDPI

Access to resources Recommend Favorite

The Involvement of Mutual Inhibition of ERK and mTOR in PLCγ1-Mediated MMP-13 Expression in Human Osteoarthritis Chondrocytes

By Liu Zejun   Cai Heguo   Zheng Xinpeng   Zhang Bing   Xia Chun  

International Journal of Molecular Sciences, Vol. 16, Iss. 8, 2015-08 ,pp. : 17857-17869 (13)

MDPI

Access to resources Recommend Favorite

Resistance to the Antiproliferative In Vitro Effect of PI3K-Akt-mTOR Inhibition in Primary Human Acute Myeloid Leukemia Cells Is Associated with Altered Cell Metabolism

By Nepstad Ina   Reikvam Håkon   Brenner Annette K.   Bruserud Øystein   Hatfield Kimberley J.  

International Journal of Molecular Sciences, Vol. 19, Iss. 2, 2018-01 ,pp. : 382-382 (1)

MDPI

Access to resources Recommend Favorite

Danusertib Induces Apoptosis, Cell Cycle Arrest, and Autophagy but Inhibits Epithelial to Mesenchymal Transition Involving PI3K/Akt/mTOR Signaling Pathway in Human Ovarian Cancer Cells

By Zi Dan   Zhou Zhi-Wei   Yang Ying-Jie   Huang Lin   Zhou Zun-Lun   He Shu-Ming   He Zhi-Xu   Zhou Shu-Feng  

International Journal of Molecular Sciences, Vol. 16, Iss. 11, 2015-11 ,pp. : 27228-27251 (24)

MDPI

Access to resources Recommend Favorite

Evodiamine Induces Apoptosis and Enhances TRAIL-Induced Apoptosis in Human Bladder Cancer Cells through mTOR/S6K1-Mediated Downregulation of Mcl-1

By Zhang Tao   Qu Shanna   Shi Qi   He Dalin   Jin Xunbo  

International Journal of Molecular Sciences, Vol. 15, Iss. 2, 2014-02 ,pp. : 3154-3171 (18)

MDPI

Access to resources Recommend Favorite