title: Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy.
abstract: Although malignant astrocytomas are a leading cause of cancer-related death in children, rational therapeutic strategies are lacking. We previously identified activating mutations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) (BRAF(T1799A) encoding BRAF(V600E)) in association with homozygous cyclin-dependent kinase inhibitor 2A (CDKN2A, encoding p14ARF and p16Ink4a) deletions in pediatric infiltrative astrocytomas. Here we report that BRAF(V600E) expression in neural progenitors (NPs) is insufficient for tumorigenesis and increases NP cellular differentiation as well as apoptosis. In contrast, astrocytomas are readily generated from NPs with additional Ink4a-Arf deletion. The BRAF(V600E) inhibitor PLX4720 significantly increased survival of mice after intracranial transplant of genetically relevant murine or human astrocytoma cells. Moreover, combination therapy using PLX4720 plus the Cyclin-dependent kinase (CDK) 4/6-specific inhibitor PD0332991 further extended survival relative to either monotherapy. Our findings indicate a rational therapeutic strategy for treating a subset of pediatric astrocytomas with BRAF(V600E) mutation and CDKN2A deficiency.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Huillard
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.forename: Amélie
authors.initials: A
authors.lastname: Griveau
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Ihrie
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Aoki
authors.forename: Theodore
authors.initials: T
authors.lastname: Nicolaides
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.forename: Todd
authors.initials: T
authors.lastname: Waldman
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Claudia
authors.initials: C
authors.lastname: Petritsch
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001254:Astrocytoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D007211:Indoles; C528407:PLX 4720; D010879:Piperazines; D011725:Pyridines; D013449:Sulfonamides; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; C500026:palbociclib