title: Combined BRAFV600Eand MEK blockade for BRAFV600E-mutant gliomas.
abstract: BRAFV600Eis a common finding in glioma (about 10-60% depending on histopathologic subclassification). BRAFV600Emonotherapy shows modest preclinical efficacy against BRAFV600Egliomas and also induces adverse secondary skin malignancies. Here, we examine the molecular mechanism of intrinsic resistance to BRAFV600Einhibition in glioma. Furthermore, we investigate BRAFV600E/MEK combination therapy that overcomes intrinsic resistance to BRAFV600Einhibitor and also prevents BRAFV600Einhibitor induced secondary malignancies. Immunoblotting and Human Phospho-Receptor Tyrosine Kinase Array assays were used to interrogate MAPK pathway activation. The cellular effect of BRAFV600Eand MEK inhibition was determined by WST-1 viability assay and cell cycle analysis. Flanked and orthotopic GBM mouse models were used to investigate the in vivo efficacy of BRAFV600E/MEK combination therapy and the effect on secondary malignancies. BRAFV600Einhibition leads to recovery of ERK phosphorylation. Combined BRAFV600Eand MEK inhibition prevents reactivation of the MAPK signaling, which correlates with decreased cell viability and augmented cell cycle arrest. Similarly, mice bearing BRAFV600Eglioma showed reduced tumor growth when treated with a combination of BRAFV600Eand MEK inhibitor compared to BRAFV600Einhibition alone. Additional benefit of BRAFV600E/MEK inhibition was reflected by reduced cutaneous squamous-cell carcinoma (cSCC) growth (a surrogate for RAS-driven secondary maligancies). In glioma, recovery of MAPK signaling upon BRAF inhibition accounts for intrinsic resistance to BRAFV600Einhibitor. Combined BRAFV600Eand MEK inhibition prevents rebound of MAPK activation, resulting in enhanced antitumor efficacy and also reduces the risk of secondary malignancy development.
authors.affiliation: Department of Pediatrics, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.
authors.forename: Tsun-Wen
authors.initials: TW
authors.lastname: Yao
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Tarry Building, 300 E Superior, Chicago, IL, 60611, USA.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.affiliation: Department of Pediatrics, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.
authors.forename: Sujatmi
authors.initials: S
authors.lastname: Hariono
authors.affiliation: Department of Neurology, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.
authors.forename: Krister J
authors.initials: KJ
authors.lastname: Barkovich
authors.affiliation: Department of Neurology, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.
authors.forename: Qi-Wen
authors.initials: QW
authors.lastname: Fan
authors.affiliation: Department of Pediatrics, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.|Department of Neurological Surgery, University of California San Francisco, 1450 3rd Street, HD400, San Francisco, CA, 94158, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Prados
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Tarry Building, 300 E Superior, Chicago, IL, 60611, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Department of Pediatrics, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.|Department of Neurology, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA.|Department of Neurological Surgery, University of California San Francisco, 1450 3rd Street, HD400, San Francisco, CA, 94158, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: Department of Pediatrics, University of California San Francisco, 1450 3rd Street, San Francisco, CA, 94158, USA. Theodore.Nicolaides@ucsf.edu.|Department of Neurological Surgery, University of California San Francisco, 1450 3rd Street, HD400, San Francisco, CA, 94158, USA. Theodore.Nicolaides@ucsf.edu.
authors.forename: Theodore
authors.initials: T
authors.lastname: Nicolaides
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; C528407:PLX 4720; D013449:Sulfonamides; C506614:mirdametinib; D004159:Diphenylamine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAFV600E; EGFR; MEK; Pediatric glioma; Secondary malignancy