title: Epithelial to mesenchymal transition is associated with rapamycin resistance.
abstract: Rapamycin analogues have antitumor efficacy in several tumor types, however few patients demonstrate tumor regression. Thus, there is a pressing need for markers of intrinsic response/resistance and rational combination therapies. We hypothesized that epithelial-to-mesenchymal transition (EMT) confers rapamycin resistance. We found that the epithelial marker E-cadherin protein is higher in rapamycin sensitive (RS) cells and mesenchymal breast cancer cell lines selected by transcriptional EMT signatures are less sensitive to rapamycin. MCF7 cells, transfected with constitutively active mutant Snail, had increased rapamycin resistance (RR) compared to cells transfected with wild-type Snail. Conversely, we transfected two RR mesenchymal cell lines-ACHN and MDA-MB-231-with miR-200b/c or ZEB1 siRNA to promote mesenchymal-to-epithelial transition. This induced E-cadherin expression in both cell lines, and ACHN demonstrated a significant increase in RS. Treatment of ACHN and MDA-MB-231 with trametinib modulated EMT in ACHN cells in vitro. Treatment of MDA-MB-231 and ACHN xenografts with trametinib in combination with rapamycin resulted in significant growth inhibition in both but without an apparent effect on EMT. Future studies are needed to determine whether EMT status is predictive of sensitivity to rapalogs and to determine whether combination therapy with EMT modulating agents can enhance antitumor effects of PI3K/mTOR inhibitors.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Surgery, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Holder
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Argun
authors.initials: A
authors.lastname: Akcakanat
authors.affiliation: Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL, USA.
authors.forename: Farrell
authors.initials: F
authors.lastname: Adkins
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kurt
authors.initials: K
authors.lastname: Evans
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Huiqin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Caimiao
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Denai R
authors.initials: DR
authors.lastname: Milton
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.affiliation: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D034622:RNA Interference; D020123:Sirolimus / Q000494:pharmacology*; D000071250:Snail Family Transcription Factors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C513384:CDH1 protein, human; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C560077:trametinib; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020123:Sirolimus
keywords: E-cadherin; biomarker; epithelial-to-mesenchymal transition (EMT); rapamycin; trametinib