title: EGFR blockade prevents glioma escape from BRAFV600E targeted therapy.
abstract: Mutational activation of BRAF(BRAF(V600E)) occurs in pediatric glioma and drives aberrant MAPK signaling independently of upstream cues. Targeted monotherapy against BRAF(V600E) displays efficacy in pre-clinical models of glioma, however xenograft tumors adapt rapidly and escape from the growth-inhibitory effects of BRAF-targeted therapy. Here, we show that intrinsic resistance to a BRAF(V600E) specific inhibitor stems, in part, from feedback activation of EGFR and downstream signaling pathways. BRAF(V600E) inhibition suppresses MAPK signaling, which in turn downregulates the EGFR phosphatase PTPN9, resulting in sustained EGFR phosphorylation and enhanced EGFR activity. We demonstrated that overexpression of PTPN9 reduces EGFR phosphorylation and cooperates with BRAF(V600E) inhibitor PLX4720 to reduce MAPK and Akt signaling, resulting in decreased glioma cell viability. Moreover, pharmacologic inhibition of EGFR combined with inhibition of BRAF(V600E) to reduce growth of glioma cell lines and orthotopic glioma xenograft by decreasing tumor cell proliferation while increasing apoptosis, with resultant significant extension of animal subject survival. Our data support clinical evaluation of BRAF(V600E) and EGFR targeted therapy in treating BRAF(V600E) glioma.
authors.affiliation: Departments of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Tsun-Wen
authors.initials: TW
authors.lastname: Yao
authors.affiliation: Departments of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Departments of Pediatrics, University of California San Francisco, San Francisco, CA, USA.|Departments of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Prados
authors.affiliation: Departments of Pediatrics, University of California San Francisco, San Francisco, CA, USA.|Departments of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.|Departments of Neurology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: Departments of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Northwestern Medicine Developmental Therapeutics Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Departments of Pediatrics, University of California San Francisco, San Francisco, CA, USA.|Departments of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Theodore
authors.initials: T
authors.lastname: Nicolaides
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011897:Random Allocation; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAFV600E; EGFR; PLX4720; PTPN9; glioma