title: Discontinuing MEK inhibitors in tumor cells with an acquired resistance increases migration and invasion.
abstract: BACKGROUND
  Development of small molecular inhibitors against BRAF and MEK has been a breakthrough in the treatment of malignant melanoma. However, the long-term effect is foiled in virtually all patients by the emergence of resistant tumor cell populations. Therefore, mechanisms resulting in the acquired resistance against BRAF and MEK inhibitors have gained much attention and several strategies have been proposed to overcome tumor resistance, including interval treatment or withdrawal of these compounds after disease progression.
  
  
  METHODS
  Using a panel of cell lines with an acquired resistance against MEK inhibitors, we have evaluated the sensitivity of these cells against compounds targeting AKT/mTOR signaling, as well as novel ERK1/2 inhibitors. Furthermore, the effects of withdrawal of MEK inhibitor on migration in resistant cell lines were analyzed.
  
  
  RESULTS
  We demonstrate that withdrawal of BRAF or MEK inhibitors in tumor cells with an acquired resistance results in reactivation of ERK1/2 signaling and upregulation of EMT-inducing transcription factors, leading to a highly migratory and invasive phenotype of cancer cells. Furthermore, we show that migration in these cells is independent from AKT/mTOR signaling. However, combined targeting of AKT/mTOR using MK-2206 and AZD8055 efficiently inhibits proliferation in all resistant tumor cell lines analyzed.
  
  
  CONCLUSIONS
  We propose that combined targeting of MEK/AKT/mTOR or treatment with a novel ERK1/2 inhibitor downstream of BRAF/MEK suppresses proliferation as well as migration and invasion in resistant tumor cells. We provide a rationale against the discontinuation of BRAF or MEK inhibitors in patients with an acquired resistance, and provide a rationale for combined targeting of AKT/mTOR and MEK/ERK1/2, or direct targeting of ERK1/2 as an effective treatment strategy.
authors.affiliation: Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: 6161867@stud.uke.uni-hamburg.de.
authors.forename: Dominik
authors.initials: D
authors.lastname: Nörz
authors.affiliation: Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: grottke.astrid@googlemail.com.
authors.forename: Astrid
authors.initials: A
authors.lastname: Grottke
authors.affiliation: Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: johanna.bach2@googlemail.com.
authors.forename: Johanna
authors.initials: J
authors.lastname: Bach
authors.affiliation: Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: christiane.herzberger@googlemail.com.
authors.forename: Christiane
authors.initials: C
authors.lastname: Herzberger
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: mail@bianca-hofmann.de.
authors.forename: Bianca T
authors.initials: BT
authors.lastname: Hofmann
authors.affiliation: Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse52, 20246 Hamburg, Germany. Electronic address: nashan@uke.de.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Nashan
authors.affiliation: Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Germany. Electronic address: juecker@uke.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jücker
authors.affiliation: Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse52, 20246 Hamburg, Germany. Electronic address: f.ewald@uke.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Ewald
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D045325:HCT116 Cells; D019073:HT29 Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000096142:Cutaneous Malignant Melanoma
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D038601:Ribosomal Protein S6; D050760:Cyclin-Dependent Kinase Inhibitor p27; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: AZD6244; Acquired resistance; BRAF; MEK; Migration