title: Activation of EIF4E by Aurora Kinase A Depicts a Novel Druggable Axis in Everolimus-Resistant Cancer Cells.
abstract: Purpose:Aurora kinase A (AURKA) is overexpressed in several cancer types, making it an attractive druggable target in clinical trials. In this study, we investigated the role of AURKA in regulating EIF4E, cap-dependent translation, and resistance to mTOR inhibitor, RAD001 (everolimus).Experimental Design:Tumor xenografts andin vitrocell models of upper gastrointestinal adenocarcinomas (UGC) were used to determine the role of AURKA in the activation of EIF4E and cap-dependent translation. Overexpression, knockdown, and pharmacologic inhibition of AURKA were usedin vitroandin vivoResults:Usingin vitrocell models, we found that high protein levels of AURKA mediate phosphorylation of EIF4E and upregulation of c-MYC. Notably, we detected overexpression of endogenous AURKA in everolimus-resistant UGC cell models. AURKA mediated phosphorylation of EIF4E, activation of cap-dependent translation, and an increase in c-MYC protein levels. Targeting AURKA using genetic knockdown or a small-molecule inhibitor, alisertib, reversed these molecular events, leading to a decrease in cancer cell survival in acquired and intrinsic resistant cell models. Mechanistic studies demonstrated that AURKA binds to and inactivates protein phosphatase 2A, a negative regulator of EIF4E, leading to phosphorylation and activation of EIF4E in an AKT-, ERK1/2-, and mTOR-independent manner. Data from tumor xenograft mouse models confirmed that everolimus-resistant cancer cells are sensitive to alisertib.Conclusions:Our results indicate that AURKA plays an important role in the activation of EIF4E and cap-dependent translation. Targeting the AURKA-EIF4E-c-MYC axis using alisertib is a novel therapeutic strategy that can be applicable for everolimus-resistant tumors and/or subgroups of cancers that show overexpression of AURKA and activation of EIF4E and c-MYC.Clin Cancer Res; 23(14); 3756-68. ©2017 AACR.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Science and Engineering, Raritan Valley Community College, Branchburg, New Jersey.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Katsha
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Lihong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Janet
authors.initials: J
authors.lastname: Arras
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Omar M
authors.initials: OM
authors.lastname: Omar
authors.affiliation: Translational Medicine, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ecsedy
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee. wael.el-rifai@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee.|Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics*; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D039561:Eukaryotic Initiation Factor-4E; C489427:MYC protein, human; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D000068338:Everolimus; C546842:MTOR protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A; D058570:TOR Serine-Threonine Kinases