title: Targeting ERK1/2 activation and proliferation in human primary schwannoma cells with MEK1/2 inhibitor AZD6244.
abstract: Deficiency of the tumor suppressor merlin leads to the development of multiple tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas. Due to the benign character of these tumors, classical chemotherapy is ineffective. Current therapies, surgery, and radiosurgery are local and quite invasive, thus new systemic treatments are required. We have previously described the Raf/mitogen-activated kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway activation and its role in schwannoma growth. Here, we targeted MEK1/2 known as a convergence point for multiple cascades towards ERK1/2 activation and cell proliferation, using MEK1/2 inhibitor AZD6244 (ARRY-142886; Astra Zeneca). We show that AZD6244 at low concentration completely abolished platelet-derived growth factor-DD-mediated ERK1/2 activation and cell proliferation in human primary schwannoma cells. Moreover, this drug was not toxic for either schwannoma or Schwann cells and has been reported to be safe with tolerable side effects. Thus, AZD6244 can be considered as a drug candidate for schwannoma treatment.
authors.affiliation: Clinical Neurobiology, Peninsula College of Medicine and Dentistry, University of Plymouth, The John Bull Building, Tamar Science Park, Research Way, Plymouth PL6 8BU, UK.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Ammoun
authors.forename: Natalia
authors.initials: N
authors.lastname: Ristic
authors.forename: Cordula
authors.initials: C
authors.lastname: Matthies
authors.forename: David A
authors.initials: DA
authors.lastname: Hilton
authors.forename: C Oliver
authors.initials: CO
authors.lastname: Hanemann
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009442:Neurilemmoma / Q000188:drug therapy* / Q000503:physiopathology*; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000502:physiology
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D010982:Platelet-Derived Growth Factor; D048052:Mitogen-Activated Protein Kinase 3; D048370:MAP Kinase Kinase 2; D001973:Bromodeoxyuridine