title: Using BRAF(V600E) as a marker of autophagy dependence in pediatric brain tumors.
abstract: Autophagy inhibition is a potential therapeutic strategy in central nervous system (CNS) tumors. The BRAF(V600E) mutation is known to affect autophagy. Our studies indicate CNS tumor cells with BRAF(V600E) mutant cells (but not wild type) display high rates of induced autophagy, are sensitive to autophagy inhibition, and display synergy when chloroquine is combined with the RAF kinase inhibitor vemurafenib or standard chemotherapeutics. Our studies also indicate chloroquine can improve vemurafenib sensitivity in intrinsically resistant cells and in a patient with induced-vemurafenib resistance. These findings suggest CNS tumors with BRAF(V600E) are autophagy-dependent and that identification of BRAF(V600E) may be a marker to identify pediatric patients with the best potential response to autophagy inhibition.
authors.affiliation: a Department of Pediatrics ; University of Colorado Denver ; Aurora , CO USA.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Mulcahy Levy
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry; D001343:Autophagy; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001933:Brain Stem / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002738:Chloroquine / Q000737:chemistry; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C000715470:MAS1 protein, human; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D013449:Sulfonamides; D000077484:Vemurafenib; D002738:Chloroquine; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; BRAF, B-Raf proto-oncogene; CNS, central nervous system; WT, wild type; autophagy; brain tumors; chloroquine; pediatric; serine/threonine kinase