title: Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma.
abstract: OBJECTIVE
  Curative therapy for childhood glioma presents challenges when complete resection is not possible. Patients with recurrent low-grade tumors or anaplastic astrocytoma may receive radiation treatment; however, the long-term sequellae from radiation treatment can be severe. As many childhood gliomas are associated with activation of BRAF, we have explored the combination of ionizing radiation with MEK inhibition in a model of BRAF-mutant anaplastic astrocytoma.
  
  
  METHODS
  The regulation of TORC1 signaling by BRAF was examined in BT-40 (BRAF mutant) and BT-35 (BRAF wild type) xenografts, in a cell line derived from the BT-40 xenograft and two adult BRAF mutant glioblastoma cell lines. The effect of MEK inhibition (selumetinib), XRT (total dose 10 Gy as 2 Gy daily fractions), or the combination of selumetinib and XRT was evaluated in subcutaneous BT-40 xenografts.
  
  
  RESULTS
  Inhibition of MEK signaling by selumetinib suppressed TORC1 signaling only in the context of the BRAF-mutant both in vitro and in vivo. Inhibition of MEK signaling in BT-40 cells or in xenografts lead to a complete suppression of FANCD2 and conferred hypersensitivity to XRT in BT-40 xenografts without increasing local skin toxicity.
  
  
  CONCLUSIONS
  Selumetinib suppressed TORC1 signaling in the context of BRAF mutation. Selumetinib caused a rapid downregulation of FANCD2 and markedly potentiated the effect of XRT. These data suggest the possibility of potentiating the effect of XRT selectively in tumor cells by MEK inhibition in the context of mutant BRAF or maintaining tumor control at lower doses of XRT that would decrease long-term sequelae.
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Adam
authors.initials: A
authors.lastname: Studebaker
authors.affiliation: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute, Columbus, Ohio.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bondra
authors.affiliation: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute, Columbus, Ohio.
authors.forename: Star
authors.initials: S
authors.lastname: Seum
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Changxian
authors.initials: C
authors.lastname: Shen
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Phelps
authors.affiliation: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute, Columbus, Ohio.
authors.forename: Christopher
authors.initials: C
authors.lastname: Chronowski
authors.affiliation: Wexner Medical Center at The Ohio State University, Arthur G. James Comprehensive Cancer Center and Richard L. Solove Research Institute, Columbus, Ohio.
authors.forename: Justin
authors.initials: J
authors.lastname: Leasure
authors.affiliation: Astrazeneca Ltd., Oncology iMed, Macclesfield, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.affiliation: Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000235:genetics* / Q000532:radiotherapy*; D001562:Benzimidazoles / Q000009:adverse effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000532:radiotherapy; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011878:Radiotherapy / Q000009:adverse effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D046912:Multiprotein Complexes; C482119:BRAF protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases
keywords: BRAF mutation; TORC1 signaling; childhood astrocytoma