EGFR blockade prevents glioma escape from BRAFV600E targeted therapy

Oncotarget. 2015 Sep 8;6(26):21993-2005. doi: 10.18632/oncotarget.4014.


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.

Keywords: BRAFV600E; EGFR; PLX4720; PTPN9; glioma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors*
  • Female
  • Glioma / drug therapy*
  • Glioma / enzymology
  • Glioma / genetics
  • Glioma / pathology
  • Humans
  • Indoles / pharmacology
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Nude
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Random Allocation
  • Signal Transduction
  • Sulfonamides / pharmacology
  • Transfection
  • Xenograft Model Antitumor Assays


  • Indoles
  • PLX 4720
  • Protein Kinase Inhibitors
  • Sulfonamides
  • EGFR protein, human
  • ErbB Receptors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf