Review Article | Published:

Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies

Oncogenevolume 37pages15611575 (2018) | Download Citation


Amplification of epidermal growth factor receptor (EGFR) and its active mutant EGFRvIII occurs frequently in glioblastoma (GBM). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs) or antibodies has only shown limited efficacy in patients. Here we discuss signaling pathways mediated by EGFR/EGFRvIII, current therapeutics, and novel strategies to target EGFR/EGFRvIII-amplified GBM.

  • Subscribe to Oncogene for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


  1. 1.

    Cloughesy TF, Cavenee WK, Mischel PS. Glioblastoma: from molecular pathology to targeted treatment. Annu Rev Pathol 2014;9:1–25.

  2. 2.

    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016;131:803–20.

  3. 3

    Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res 2013;19:764–72.

  4. 4.

    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010;17:98–110.

  5. 5.

    Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014;344:1396–401.

  6. 6.

    Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell 2013;155:462–77.

  7. 7.

    Jawhari S, Ratinaud MH, Verdier M, Glioblastoma, hypoxia and autophagy: a survival-prone ‘menage-a-trois’. Cell Death Dis. 2016;7:e2434

  8. 8.

    Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 2014;25:282–303.

  9. 9.

    Singh B, Coffey RJ. Trafficking of epidermal growth factor receptor ligands in polarized epithelial cells. Annu Rev Physiol 2014;76:275–300.

  10. 10.

    Mayer BJ. The discovery of modular binding domains: building blocks of cell signalling. Nat Rev Mol Cell Biol 2015;16:691–8.

  11. 11.

    Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 2015;15:7–24.

  12. 12.

    Furnari FB, Cloughesy TF, Cavenee WK, Mischel PS. Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma. Nat Rev Cancer 2015;15:302–10.

  13. 13.

    Eskilsson E, Rosland GV, Talasila KM, Knappskog S, Keunen O, Sottoriva A, et al. EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation. Neuro Oncol 2016;18:1644–55.

  14. 14.

    Sugawa N, Ekstrand AJ, James CD, Collins VP. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc Natl Acad Sci USA 1990;87:8602–6.

  15. 15.

    Guo G, Gong K, Wohlfeld B, Hatanpaa KJ, Zhao D, Habib AA. Ligand-independent EGFR signaling. Cancer Res 2015;75:3436–41.

  16. 16.

    Huang HS, Nagane M, Klingbeil CK, Lin H, Nishikawa R, Ji XD, et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem 1997;272:2927–35.

  17. 17.

    Fan QW, Cheng CK, Gustafson WC, Charron E, Zipper P, Wong RA, et al. EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell 2013;24:438–49.

  18. 18.

    Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS, et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ 1995;6:1251–9.

  19. 19.

    Moscatello DK, Montgomery RB, Sundareshan P, McDanel H, Wong MY, Wong AJ. Transformational and altered signal transduction by a naturally occurring mutant EGF receptor. Oncogene 1996;13:85–96.

  20. 20.

    Boyd PS, Struve N, Bach M, Eberle JP, Gote M, Schock F, et al. Clustered localization of EGFRvIII in glioblastoma cells as detected by high precision localization microscopy. Nanoscale 2016;8:20037–47.

  21. 21.

    Ekstrand AJ, Liu L, He J, Hamid ML, Longo N, Collins VP, et al. Altered subcellular location of an activated and tumour-associated epidermal growth factor receptor. Oncogene 1995;10:1455–60.

  22. 22.

    Pedersen MW, Tkach V, Pedersen N, Berezin V, Poulsen HS. Expression of a naturally occurring constitutively active variant of the epidermal growth factor receptor in mouse fibroblasts increases motility. Int J Cancer 2004;108:643–53.

  23. 23.

    Feng H, Hu B, Vuori K, Sarkaria JN, Furnari FB, Cavenee WK, et al. EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180. Oncogene 2014;33:2504–12.

  24. 24.

    Bonavia R, Inda MM, Vandenberg S, Cheng SY, Nagane M, Hadwiger P, et al. EGFRvIII promotes glioma angiogenesis and growth through the NF-kappaB, interleukin-8 pathway. Oncogene 2012;31:4054–66.

  25. 25.

    Katanasaka Y, Kodera Y, Kitamura Y, Morimoto T, Tamura T, Koizumi F. Epidermal growth factor receptor variant type III markedly accelerates angiogenesis and tumor growth via inducing c-myc mediated angiopoietin-like 4 expression in malignant glioma. Mol Cancer 2013;12:31.

  26. 26.

    Congdon KL, Gedeon PC, Suryadevara CM, Caruso HG, Cooper LJ, Heimberger AB, et al. Epidermal growth factor receptor and variant III targeted immunotherapy. Neuro Oncol 2014;16(Suppl 8):viii20–25.

  27. 27.

    Malkki H. Trial watch: glioblastoma vaccine therapy disappointment in Phase III trial. Nat Rev Neurol 2016;12:190.

  28. 28.

    Nathanson DA, Gini B, Mottahedeh J, Visnyei K, Koga T, Gomez G, et al. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 2014;343:72–76.

  29. 29.

    Papke B, Der CJ. Drugging RAS: know the enemy. Science 2017;355:1158–63.

  30. 30.

    Kolch W, Halasz M, Granovskaya M, Kholodenko BN. The dynamic control of signal transduction networks in cancer cells. Nat Rev Cancer 2015;15:515–27.

  31. 31.

    Deschenes-Simard X, Kottakis F, Meloche S, Ferbeyre G. ERKs in cancer: friends or foes? Cancer Res 2014;74:412–9.

  32. 32.

    Spiegel J, Cromm PM, Zimmermann G, Grossmann TN, Waldmann H. Small-molecule modulation of Ras signaling. Nat Chem Biol 2014;10:613–22.

  33. 33.

    Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455:1061–8.

  34. 34

    Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 2000;25:55–57.

  35. 35.

    Unni AM, Lockwood WW, Zejnullahu K, Lee-Lin SQ, Varmus H, Evidence that synthetic lethality underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma. Elife. 2015;e06907.

  36. 36.

    Klempner SJ, Myers AP, Cantley LC. What a tangled web we weave: emerging resistance mechanisms to inhibition of the phosphoinositide 3-kinase pathway. Cancer Discov 2013;3:1345–54.

  37. 37.

    Mattoon DR, Lamothe B, Lax I, Schlessinger J. The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway. BMC Biol 2004;2:24.

  38. 38.

    Ozawa T, Riester M, Cheng YK, Huse JT, Squatrito M, Helmy K, et al. Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma. Cancer Cell 2014;26:288–300.

  39. 39.

    Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648–57.

  40. 40.

    Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997;91:231–41.

  41. 41.

    Wang RC, Wei Y, An Z, Zou Z, Xiao G, Bhagat G, et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 2012;338:956–9.

  42. 42.

    Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science 1998;282:1318–21.

  43. 43.

    Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999;401:82–85.

  44. 44.

    Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 1998;273:32377–9.

  45. 45.

    Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857–68.

  46. 46.

    Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol 2003;23:7315–28.

  47. 47.

    Novellasdemunt L, Tato I, Navarro-Sabate A, Ruiz-Meana M, Mendez-Lucas A, Perales JC, et al. Akt-dependent activation of the heart 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB2) isoenzyme by amino acids. J Biol Chem 2013;288:10640–51.

  48. 48.

    Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, et al. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab 2014;20:306–19.

  49. 49.

    He K, Qi Q, Chan CB, Xiao G, Liu X, Tucker-Burden C, et al. Blockade of glioma proliferation through allosteric inhibition of JAK2. Sci Signal 2013;6:ra55.

  50. 50.

    O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med 2015;66:311–28.

  51. 51.

    Park OK, Schaefer TS, Nathans D. In vitro activation of Stat3 by epidermal growth factor receptor kinase. Proc Natl Acad Sci USA 1996;93:13704–8.

  52. 52.

    Wen Z, Zhong Z, Darnell JE Jr.. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 1995;82:241–50.

  53. 53.

    Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N, et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 2013;23:839–52.

  54. 54.

    de la Iglesia N, Konopka G, Puram SV, Chan JA, Bachoo RM, You MJ, et al. Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev 2008;22:449–62.

  55. 55.

    Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature 2010;463:318–25.

  56. 56.

    See AP, Han JE, Phallen J, Binder Z, Gallia G, Pan F, et al. The role of STAT3 activation in modulating the immune microenvironment of GBM. J Neurooncol 2012;110:359–68.

  57. 57.

    Gong AH, Wei P, Zhang S, Yao J, Yuan Y, Zhou AD, et al. FoxM1 drives a feed-forward STAT3-activation signaling loop that promotes the self-renewal and tumorigenicity of glioblastoma stem-like cells. Cancer Res 2015;75:2337–48.

  58. 58.

    Garner JM, Fan M, Yang CH, Du Z, Sims M, Davidoff AM, et al. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappaB signaling in glioblastoma cancer stem cells regulates the Notch pathway. J Biol Chem 2013;288:26167–76.

  59. 59.

    Lo HW, Cao X, Zhu H, Ali-Osman F. Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Cancer Res 2008;14:6042–54.

  60. 60.

    Kadamur G, Ross EM. Mammalian phospholipase C. Annu Rev Physiol 2013;75:127–54.

  61. 61.

    Garg R, Benedetti LG, Abera MB, Wang H, Abba M, Kazanietz MG. Protein kinase C and cancer: what we know and what we do not. Oncogene 2014;33:5225–37.

  62. 62.

    Antal CE, Hudson AM, Kang E, Zanca C, Wirth C, Stephenson NL, et al. Cancer-associated protein kinase C mutations reveal kinase’s role as tumor suppressor. Cell 2015;160:489–502.

  63. 63.

    Ma L, Tao Y, Duran A, Llado V, Galvez A, Barger JF, et al. Control of nutrient stress-induced metabolic reprogramming by PKCzeta in tumorigenesis. Cell 2013;152:599–611.

  64. 64.

    Fan QW, Cheng C, Knight ZA, Haas-Kogan D, Stokoe D, James CD, et al. EGFR signals to mTOR through PKC and independently of Akt in glioma. Sci Signal 2009;2:ra4.

  65. 65.

    Uht RM, Amos S, Martin PM, Riggan AE, Hussaini IM. The protein kinase C-eta isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway. Oncogene 2007;26:2885–93.

  66. 66.

    Aeder SE, Martin PM, Soh JW, Hussaini IM. PKC-eta mediates glioblastoma cell proliferation through the Akt and mTOR signaling pathways. Oncogene 2004;23:9062–9.

  67. 67.

    Amos S, Martin PM, Polar GA, Parsons SJ, Hussaini IM. Phorbol 12-myristate 13-acetate induces epidermal growth factor receptor transactivation via protein kinase Cdelta/c-Src pathways in glioblastoma cells. J Biol Chem 2005;280:7729–38.

  68. 68.

    Mawrin C, Diete S, Treuheit T, Kropf S, Vorwerk CK, Boltze C, et al. Prognostic relevance of MAPK expression in glioblastoma multiforme. Int J Oncol 2003;23:641–8.

  69. 69.

    Boerner JL, Demory ML, Silva C, Parsons SJ. Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II. Mol Cell Biol 2004;24:7059–71.

  70. 70.

    Wang SC, Hung MC. Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors. Clin Cancer Res 2009;15:6484–9.

  71. 71.

    Liccardi G, Hartley JA, Hochhauser D. EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. Cancer Res 2011;71:1103–14.

  72. 72.

    Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, et al. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol 2006;8:1359–68.

  73. 73.

    Chou RH, Wang YN, Hsieh YH, Li LY, Xia W, Chang WC, et al. EGFR modulates DNA synthesis and repair through Tyr phosphorylation of histone H4. Dev Cell 2014;30:224–37.

  74. 74.

    Er EE, Mendoza MC, Mackey AM, Rameh LE, Blenis J. AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve. Sci Signal 2013;6:ra45.

  75. 75.

    Kim J, Jahng WJ, Di Vizio D, Lee JS, Jhaveri R, Rubin MA, et al. The phosphoinositide kinase PIKfyve mediates epidermal growth factor receptor trafficking to the nucleus. Cancer Res 2007;67:9229–37.

  76. 76.

    Brand TM, Iida M, Corrigan KL, Braverman CM, Coan JP, Flanigan BG, et al. The receptor tyrosine kinase AXL mediates nuclear translocation of the epidermal growth factor receptor. Sci Signal 2017;10:eaag1064.

  77. 77.

    Lo HW, Cao X, Zhu H, Ali-Osman F. Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFRvIII-STAT3 signaling axes. Mol Cancer Res 2010;8:232–45.

  78. 78.

    Latha K, Li M, Chumbalkar V, Gururaj A, Hwang Y, Dakeng S, et al. Nuclear EGFRvIII-STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl-XL promoter. Int J Cancer 2013;132:509–20.

  79. 79.

    Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 2003;63:6962–70.

  80. 80.

    Nagane M, Coufal F, Lin H, Bogler O, Cavenee WK, Huang HJ. A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Res 1996;56:5079–86.

  81. 81.

    Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA 1994;91:7727–31.

  82. 82.

    Babic I, Anderson ES, Tanaka K, Guo D, Masui K, Li B, et al. EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab 2013;17:1000–8.

  83. 83.

    Grandal MV, Zandi R, Pedersen MW, Willumsen BM, van Deurs B, Poulsen HS. EGFRvIII escapes down-regulation due to impaired internalization and sorting to lysosomes. Carcinogenesis 2007;28:1408–17.

  84. 84.

    Liu F, Hon GC, Villa GR, Turner KM, Ikegami S, Yang H, et al. EGFR mutation promotes glioblastoma through epigenome and transcription factor network remodeling. Mol Cell 2015;60:307–18.

  85. 85.

    Feng H, Hu B, Jarzynka MJ, Li Y, Keezer S, Johns TG, et al. Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis. Proc Natl Acad Sci USA 2012;109:3018–23.

  86. 86.

    Jahani-Asl A, Yin H, Soleimani VD, Haque T, Luchman HA, Chang NC, et al. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat Neurosci 2016;19:798–806.

  87. 87.

    Cvrljevic AN, Akhavan D, Wu M, Martinello P, Furnari FB, Johnston AJ, et al. Activation of Src induces mitochondrial localisation of de2-7EGFR (EGFRvIII) in glioma cells: implications for glucose metabolism. J Cell Sci 2011;124:2938–50.

  88. 88.

    Greenall SA, Donoghue JF, Van Sinderen M, Dubljevic V, Budiman S, Devlin M, et al. EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications. Oncogene 2015;34:5277–87.

  89. 89.

    Garnett J, Chumbalkar V, Vaillant B, Gururaj AE, Hill KS, Latha K, et al. Regulation of HGF expression by DeltaEGFR-mediated c-Met activation in glioblastoma cells. Neoplasia 2013;15:73–84.

  90. 90.

    Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, et al. Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc Natl Acad Sci USA 2006;103:17402–7.

  91. 91.

    Lal A, Glazer CA, Martinson HM, Friedman HS, Archer GE, Sampson JH, et al. Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Res 2002;62:3335–9.

  92. 92.

    Inda MM, Bonavia R, Mukasa A, Narita Y, Sah DW, Vandenberg S, et al. Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma. Genes Dev 2010;24:1731–45.

  93. 93.

    Holland EC, Hively WP, DePinho RA, Varmus HE. A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice. Genes Dev 1998;12:3675–85.

  94. 94.

    Weiss WA, Burns MJ, Hackett C, Aldape K, Hill JR, Kuriyama H, et al. Genetic determinants of malignancy in a mouse model for oligodendroglioma. Cancer Res 2003;63:1589–95.

  95. 95.

    Ding H, Shannon P, Lau N, Wu X, Roncari L, Baldwin RL, et al. Oligodendrogliomas result from the expression of an activated mutant epidermal growth factor receptor in a RAS transgenic mouse astrocytoma model. Cancer Res 2003;63:1106–13.

  96. 96.

    Ramnarain DB, Park S, Lee DY, Hatanpaa KJ, Scoggin SO, Otu H, et al. Differential gene expression analysis reveals generation of an autocrine loop by a mutant epidermal growth factor receptor in glioma cells. Cancer Res 2006;66:867–74.

  97. 97.

    Kancha RK, von Bubnoff N, Duyster J. Asymmetric kinase dimer formation is crucial for the activation of oncogenic EGFRvIII but not for ERBB3 phosphorylation. Cell Commun Signal 2013;11:39.

  98. 98.

    Li L, Chakraborty S, Yang CR, Hatanpaa KJ, Cipher DJ, Puliyappadamba VT, et al. An EGFR wild type-EGFRvIII-HB-EGF feed-forward loop regulates the activation of EGFRvIII. Oncogene 2014;33:4253–64.

  99. 99.

    Luwor RB, Zhu HJ, Walker F, Vitali AA, Perera RM, Burgess AW, et al. The tumor-specific de2-7 epidermal growth factor receptor (EGFR) promotes cells survival and heterodimerizes with the wild-type EGFR. Oncogene 2004;23:6095–104.

  100. 100.

    Hwang Y, Chumbalkar V, Latha K, Bogler O. Forced dimerization increases the activity of DeltaEGFR/EGFRvIII and enhances its oncogenicity. Mol Cancer Res 2011;9:1199–208.

  101. 101.

    Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 2008;10:619–24.

  102. 102.

    Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008;10:1470–6.

  103. 103.

    Francis JM, Zhang CZ, Maire CL, Jung J, Manzo VE, Adalsteinsson VA, et al. EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov 2014;4:956–71.

  104. 104.

    Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 2007;318:287–90.

  105. 105.

    Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci USA 2012;109:3041–6.

  106. 106.

    Akhavan D, Pourzia AL, Nourian AA, Williams KJ, Nathanson D, Babic I, et al. De-repression of PDGFRbeta transcriptionpromotes acquired resistance to EGFR tyrosine kinase inhibitorsin glioblastoma patients. Cancer Discov. 2013;3:534–47.

  107. 107.

    Clark PA, Iida M, Treisman DM, Kalluri H, Ezhilan S, Zorniak M, et al. Activation of multiple ERBB family receptors mediates glioblastoma cancer stem-like cell resistance to EGFR-targeted inhibition. Neoplasia 2012;14:420–8.

  108. 108.

    Halatsch ME, Gehrke EE, Vougioukas VI, Botefur IC, A-Borhani F, Efferth T, et al. Inverse correlation of epidermal growth factor receptor messenger RNA induction and suppression of anchorage-independent growth by OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines. J Neurosurg 2004;100:523–33.

  109. 109.

    Reardon DA, Groves MD, Wen PY, Nabors L, Mikkelsen T, Rosenfeld S, et al. A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. Clin Cancer Res 2013;19:900–8.

  110. 110.

    Rosell R, Taron M, Reguart N, Isla D, Moran T. Epidermal growth factor receptor activation: how exon 19 and 21 mutations changed our understanding of the pathway. Clin Cancer Res 2006;12:7222–31.

  111. 111.

    Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010;467:596–9.

  112. 112.

    Vivanco I, Robins HI, Rohle D, Campos C, Grommes C, Nghiemphu PL, et al. Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors. Cancer Discov 2012;2:458–71.

  113. 113.

    Barkovich KJ, Hariono S, Garske AL, Zhang J, Blair JA, Fan QW, et al. Kinetics of inhibitor cycling underlie therapeutic disparities between EGFR-driven lung and brain cancers. Cancer Discov 2012;2:450–7.

  114. 114.

    Roth P, Weller M. Challenges to targeting epidermal growth factor receptor in glioblastoma: escape mechanisms and combinatorial treatment strategies. Neuro Oncol 2014;16(Suppl 8):viii14–19.

  115. 115.

    Reardon DA, Nabors LB, Mason WP, Perry JR, Shapiro W, Kavan P, et al. Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma. Neuro Oncol 2015;17:430–9.

  116. 116.

    Zahonero C, Aguilera P, Ramirez-Castillejo C, Pajares M, Bolos MV, Cantero D, et al. Preclinical test of dacomitinib, an irreversible EGFR inhibitor, confirms its effectiveness for glioblastoma. Mol Cancer Ther 2015;14:1548–58.

  117. 117.

    Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046–61.

  118. 118.

    Tan CS, Gilligan D, Pacey S. Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol 2015;16:e447–459.

  119. 119.

    Gan HK, Burgess AW, Clayton AH, Scott AM. Targeting of a conformationally exposed, tumor-specific epitope of EGFR as a strategy for cancer therapy. Cancer Res 2012;72:2924–30.

  120. 120.

    Dreier A, Barth S, Goswami A, Weis J. Cetuximab induces mitochondrial translocalization of EGFRvIII, but not EGFR: involvement of mitochondria in tumor drug resistance? Tumour Biol 2012;33:85–94.

  121. 121.

    Chong DQ, Toh XY, Ho IA, Sia KC, Newman JP, Yulyana Y, et al. Combined treatment of Nimotuzumab and rapamycin is effective against temozolomide-resistant human gliomas regardless of the EGFR mutation status. BMC Cancer 2015;15:255.

  122. 122.

    Neyns B, Sadones J, Joosens E, Bouttens F, Verbeke L, Baurain JF, et al. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol 2009;20:1596–603.

  123. 123.

    Cleary JM, Reardon DA, Azad N, Gandhi L, Shapiro GI, Chaves J, et al. A phase 1 study of ABT-806 in subjects with advanced solid tumors. Invest New Drugs 2015;33:671–8.

  124. 124.

    Li L, Quang TS, Gracely EJ, Kim JH, Emrich JG, Yaeger TE, et al. A Phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme. J Neurosurg 2010;113:192–8.

  125. 125.

    Holliger P, Hudson PJ. Engineered antibody fragments and the rise of single domains. Nat Biotechnol 2005;23:1126–36.

  126. 126.

    Choi BD, Kuan CT, Cai M, Archer GE, Mitchell DA, Gedeon PC, et al. Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma. Proc Natl Acad Sci USA 2013;110:270–5.

  127. 127.

    Fousek K, Ahmed N. The evolution of T-cell therapies for solid malignancies. Clin Cancer Res 2015;21:3384–92.

  128. 128.

    Appelboom G, Detappe A, LoPresti M, Kunjachan S, Mitrasinovic S, Goldman S, et al. Stereotactic modulation of blood-brain barrier permeability to enhance drug delivery. Neuro Oncol 2016;18:1601–9.

  129. 129.

    Schijns VE, Pretto C, Devillers L, Pierre D, Hofman FM, Chen TC, et al. First clinical results of a personalized immunotherapeutic vaccine against recurrent, incompletely resected, treatment-resistant glioblastoma multiforme (GBM) tumors, based on combined allo- and auto-immune tumor reactivity. Vaccine 2015;33:2690–6.

  130. 130.

    Swartz AM, Li QJ, Sampson JH. Rindopepimut: a promising immunotherapeutic for the treatment of glioblastoma multiforme. Immunotherapy 2014;6:679–90.

  131. 131.

    Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE 2nd, Lally-Goss D, et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther 2009;8:2773–9.

  132. 132.

    Schuster J, Lai RK, Recht LD, Reardon DA, Paleologos NA, Groves MD, et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol 2015;17:854–61.

  133. 133.

    Zussman BM, Engh JA. Outcomes of the ACT III study: rindopepimut (CDX-110) therapy for glioblastoma. Neurosurgery 2015;76:N17.

  134. 134.

    Johnson LA, Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med 2015;7:275ra222.

  135. 135.

    Han J, Chu J, Keung Chan W, Zhang J, Wang Y, Cohen JB, et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci Rep 2015;5:11483.

  136. 136.

    Chow KH, Gottschalk S. Cellular immunotherapy for high-grade glioma. Immunotherapy 2011;3:423–34.

  137. 137.

    Shir A, Levitzki A. Inhibition of glioma growth by tumor-specific activation of double-stranded RNA-dependent protein kinase PKR. Nat Biotechnol 2002;20:895–900.

  138. 138.

    Halatsch ME, Schmidt U, Botefur IC, Holland JF, Ohnuma T. Marked inhibition of glioblastoma target cell tumorigenicity in vitro by retrovirus-mediated transfer of a hairpin ribozyme against deletion-mutant epidermal growth factor receptor messenger RNA. J Neurosurg 2000;92:297–305.

  139. 139.

    Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 2003;22:2812–22.

  140. 140.

    Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 2005;353:2012–24.

  141. 141.

    Fenton TR, Nathanson D, Ponte de Albuquerque C, Kuga D, Iwanami A, Dang J, et al. Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240. Proc Natl Acad Sci USA 2012;109:14164–9.

  142. 142.

    Iwanami A, Gini B, Zanca C, Matsutani T, Assuncao A, Nael A, et al. PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. Proc Natl Acad Sci USA 2013;110:4339–44.

  143. 143.

    Chakravarti A, Loeffler JS, Dyson NJ. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 2002;62:200–7.

  144. 144.

    Jun HJ, Bronson RT, Charest A. Inhibition of EGFR induces a c-MET-driven stem cell population in glioblastoma. Stem Cells 2014;32:338–48.

  145. 145.

    Li L, Puliyappadamba VT, Chakraborty S, Rehman A, Vemireddy V, Saha D, et al. EGFR wild type antagonizes EGFRvIII-mediated activation of Met in glioblastoma. Oncogene 2015;34:129–34.

  146. 146.

    Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 2011;20:810–7.

  147. 147.

    Turner KM, Deshpande V, Beyter D, Koga T, Rusert J, Lee C, et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 2017;543:122–5.

  148. 148.

    Li W, Graeber MB. The molecular profile of microglia under the influence of glioma. Neuro Oncol 2012;14:958–78.

  149. 149.

    Miller TE, Liau BB, Wallace LC, Morton AR, Xie Q, Dixit D, et al. Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature 2017;547:355–9.

Download references


ZA is supported by the Alex’s Lemonade Stand Foundation and by Program for Breakthrough Biomedical Research, which is partially funded by the Sandler Foundation. The Weiss lab is supported by NIH grants CA148699, NS091620, NS0883555, NS089868, CA183692, CA176287, and CA82103; the Alex’s Lemonade Stand, Children’s Tumor, Katie Dougherty, Pediatric Brain Tumor, Ross K. MacNeill, St. Baldrick, and Samuel G. Waxman Foundations; and the Evelyn and Mattie Anderson Chair.

Author information


  1. Department of Neurology, University of California, San Francisco, CA, USA

    • Zhenyi An
    • , Ozlem Aksoy
    • , Tina Zheng
    • , Qi-Wen Fan
    •  & William A. Weiss
  2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA

    • William A. Weiss
  3. Department of Neurological Surgery, University of California, San Francisco, CA, USA

    • William A. Weiss


  1. Search for Zhenyi An in:

  2. Search for Ozlem Aksoy in:

  3. Search for Tina Zheng in:

  4. Search for Qi-Wen Fan in:

  5. Search for William A. Weiss in:

Conflict of interest

The authors declare that they have no ccompeting interests.

Corresponding author

Correspondence to William A. Weiss.

About this article

Publication history






Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.