title: mTOR inhibition induces EGFR feedback activation in association with its resistance to human pancreatic cancer.
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.
authors: Department of Hepatobiliary and Pancreas Surgery, the First Hospital, Jilin University, Changchun 130021, China. wei_feng@jlu.edu.cn.
authors: Feng
authors: F
authors: Wei
authors: Department of Hepatobiliary and Pancreas Surgery, the First Hospital, Jilin University, Changchun 130021, China. zhangyd78@126.com.
authors: Yandong
authors: Y
authors: Zhang
authors: Department of General Surgery, the Second Hospital of Jilin University, Changchun 130041, China. gengli79@gmail.com.
authors: Li
authors: L
authors: Geng
authors: Department of Hepatobiliary and Pancreas Surgery, the First Hospital, Jilin University, Changchun 130021, China. azhangpinga@126.com.
authors: Ping
authors: P
authors: Zhang
authors: Department of Hepatobiliary and Pancreas Surgery, the First Hospital, Jilin University, Changchun 130021, China. wgymd1956@163.com.
authors: Guangyi
authors: G
authors: Wang
authors: Genetic Engineering Laboratory of PLA, the Eleventh Institute of Academy of Military Medical Sciences of PLA, Changchun 130122, China. liu820512@163.com.
authors: Yan
authors: Y
authors: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051858:Forkhead Transcription Factors; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
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