Medical Oncology

, 35:122 | Cite as

Receptor tyrosine kinase-Ras-PI 3 kinase-Akt signaling network in glioblastoma multiforme

  • Gulten Tuncel
  • Rasime KalkanEmail author
Review Article


Glioblastoma multiforme (GBM) is the most malignant form of the brain tumors and shows different genetic and epigenetic abnormalities. Gene amplification, genetic instability, disruption of apoptotic pathways, deregulated oncogene expression, invasive phenotypical changes, abnormal angiogenesis, and epigenetic changes have all been described in GBMs. These abnormalities indicate that a number of different signaling pathways are deregulated in GBM. Increasing number of studies provide a better understanding of the tumor biology, genetic, and epigenetic background of the GBM. Also, current research provides us useful approaches in designing novel therapies for GBM. In this review, we summarize the receptor tyrosine kinase-Ras-PI 3 kinase-Akt signaling network, focusing on the potential molecular targets for anti-signaling molecular therapies in this pathway.


Glioblastoma Molecular target Receptor tyrosine kinase Ras PI 3 kinase-Akt 


Compliance with ethical standards

Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in this manuscript.


  1. 1.
    Abounader R, Laterra J: Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis. Neuro-oncology. 2005;7(4):436–51.CrossRefGoogle Scholar
  2. 2.
    Agliano A, Balarajah G, Ciobota DM, Sidhu J, Clarke PA, Jones C, Workman P, Leach MO, Al-Saffar NMS. Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy. Oncotarget. 2017;8(29):47969–83.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Amatya VJ, Naumann U, Weller M, Ohgaki H: TP53 promoter methylation in human gliomas. Acta Neuropathol. 2005;110(2):178–84.CrossRefGoogle Scholar
  4. 4.
    Arvanitis D, Malliri A, Antoniou D, Linardopoulos S, Field JK, Spandidos DA: Ras p21 expression in brain tumors: elevated expression in malignant astrocytomas and glioblastomas multiforme. In Vivo. 1991;5(4):317–21.Google Scholar
  5. 5.
    Assem M, Sibenaller Z, Agarwal S, Al-Keilani MS, Alqudah MA, Ryken TC: Enhancing diagnosis, prognosis, and therapeutic outcome prediction of gliomas using genomics. Omics. 2012;16(3):113–22.CrossRefGoogle Scholar
  6. 6.
    Becker D, Lee PL, Rodeck U, Herlyn M. Inhibition of the fibroblast growth factor receptor 1 (FGFR-1) gene in human melanocytes and malignant melanomas leads to inhibition of proliferation and signs indicative of differentiation. Oncogene. 1992;7(11):2303–13.PubMedGoogle Scholar
  7. 7.
    Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011;71(13):4366–72.PubMedCrossRefGoogle Scholar
  8. 8.
    Biggs WH 3rd, Meisenhelder J, Hunter T, Cavenee WK, Arden KC. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA. 1999;96(13):7421–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Bleeker FE, Molenaar RJ, Leenstra S. Recent advances in the molecular understanding of glioblastoma. J Neurooncol. 2012;108(1):11–27.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bos JL. ras oncogenes in human cancer: a review. Cancer Res. 1989;49(17):4682–9.PubMedGoogle Scholar
  11. 11.
    Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O’Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L: The somatic genomic landscape of glioblastoma. Cell. 2013;155(2):462–77.CrossRefGoogle Scholar
  12. 12.
    Burgering BM, Kops GJ: Cell cycle and death control: long live Forkheads. Trends Biochem Sci. 2002;27(7):352–60.CrossRefGoogle Scholar
  13. 13.
    Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296(5573):1655–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Castellano E, Downward J: RAS interaction with PI3K: more than just another effector pathway. Genes Cancer. 2001;2(3):261–74.Google Scholar
  15. 15.
    Cecchi F, Rabe DC, Bottaro DP: The hepatocyte growth factor receptor: structure, function and pharmacological targeting in cancer. Curr Signal Transduct Ther. 2011;6(2):146–51.CrossRefGoogle Scholar
  16. 16.
    Chae YK, Ranganath K, Hammerman PS, Vaklavas C, Mohindra N, Kalyan A, Matsangou M, Costa R, Carneiro B, Villaflor VM, Cristofanilli M, Giles FJ. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. Oncotarget. 2017;8(9):16052–74.PubMedCrossRefGoogle Scholar
  17. 17.
    Chakravarti A, Zhai G, Suzuki Y, Sarkesh S, Black PM, Muzikansky A, Loeffler JS. The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J Clin Oncol. 2004;22(10):1926–33.PubMedCrossRefGoogle Scholar
  18. 18.
    Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, Hambardzumyan D, Holland EC: Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell. 2010;6(2):141–52.CrossRefGoogle Scholar
  19. 19.
    Choe G, Horvath S, Cloughesy TF, Crosby K, Seligson D, Palotie A, Inge L, Smith BL, Sawyers CL, Mischel PS. Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res. 2003;63(11):2742–6.PubMedGoogle Scholar
  20. 20.
    Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 2008;5(1):e8.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Danilkovitch-Miagkova A, Zbar B. Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Investig. 2002;109(7):863–7.PubMedCrossRefGoogle Scholar
  22. 22.
    de Groot JF, Lamborn KR, Chang SM, Gilbert MR, Cloughesy TF, Aldape K, Yao J, Jackson EF, Lieberman F, Robins HI, Mehta MP, Lassman AB, Deangelis LM, Yung WK, Chen A, Prados MD, Wen PY. Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium Study. J Clin Oncol. 2011;29(19):2689–95.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Del Vecchio CA, Giacomini CP, Vogel H, Jensen KC, Florio T, Merlo A, Pollack JR, Wong AJ. EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene. 2013;32(21):2670–81.PubMedCrossRefGoogle Scholar
  24. 24.
    Ding H, Roncari L, Shannon P, Wu X, Lau N, Karaskova J, Gutmann DH, Squire JA, Nagy A, Guha A. Astrocyte-specific expression of activated p21-Ras results in malignant astrocytoma formation in a transgenic mouse model of human gliomas. Cancer Res. 2001;61(9):3826–36.PubMedGoogle Scholar
  25. 25.
    Ding L, Wang S, Wang W, Lv P, Zhao D, Chen F, Meng T, Dong L, Qi L. Tanshinone IIA affects autophagy and apoptosis of glioma cells by inhibiting phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway. Pharmacology. 2017;99(3–4):188–95.PubMedCrossRefGoogle Scholar
  26. 26.
    Ducassou A, Uro-Coste E, Verrelle P, Filleron T, Benouaich-Amiel A, Lubrano V, Sol JC, Delisle MB, Favre G, Ken S, Laprie A, De Porre P, Toulas C, Poublanc M, Cohen-Jonathan Moyal E. αvβ3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): prognostic factors in a phase I-II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma. Eur J Cancer. 2013;49(9):2161–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Duerr EM, Rollbrocker B, Hayashi Y, Peters N, Meyer-Puttlitz B, Louis DN, Schramm J, Wiestler OD, Parsons R, Eng C, von Deimling A: PTEN mutations in gliomas and glioneuronal tumors. Oncogene. 1998;16(17):2259–64.PubMedCrossRefGoogle Scholar
  28. 28.
    Duzgun Z, Eroglu Z, Biray Avci C: Role of mTOR in glioblastoma. Gene. 2016;575(2 Pt 1):187–90.Google Scholar
  29. 29.
    Fleming TP, Saxena A, Clark WC, Robertson JT, Oldfield EH, Aaronson SA, Ali IU. Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res. 1992;52(16):4550–3.PubMedGoogle Scholar
  30. 30.
    Friedman HS, Kerby T, Calvert H. Temozolomide and treatment of malignant glioma. Clin Cancer Res. 2000;6(7):2585–97.PubMedGoogle Scholar
  31. 31.
    Funa K, Sasahara M: The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system. J Neuroimmune Pharmacol. 2014;9(2):168–81.CrossRefGoogle Scholar
  32. 32.
    Furnari FB, Huang HJ, Cavenee WK. The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res. 1998;58(22):5002–8.PubMedGoogle Scholar
  33. 33.
    Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280(21):5350–70.PubMedCrossRefGoogle Scholar
  34. 34.
    Gao Q, Lei T, Ye F. Therapeutic targeting of EGFR-activated metabolic pathways in glioblastoma. Expert Opin Investig Drugs. 2013;22(8):1023–40.PubMedCrossRefGoogle Scholar
  35. 35.
    Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699–708.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Giordano S: Rilotumumab, a mAb against human hepatocyte growth factor for the treatment of cancer. Curr Opin Mol Ther. 2009;11(4):448–55.Google Scholar
  37. 37.
    Gopinath S, Malla RR, Gondi CS, Alapati K, Fassett D, Klopfenstein JD, Dinh DH, Gujrati M, Rao JS. Co-depletion of cathepsin B and uPAR induces G0/G1 arrest in glioma via FOXO3a mediated p27 upregulation. PLoS ONE. 2010;5(7):e11668.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Gouaze-Andersson V, Delmas C, Taurand M, Martinez-Gala J, Evrard S, Mazoyer S, Toulas C, Cohen-Jonathan-Moyal E: FGFR1 induces glioblastoma radioresistance through the PLCγ/Hif1α pathway. Cancer Res. 2016;76(10):3036–44.PubMedCrossRefGoogle Scholar
  39. 39.
    Heimberger AB, Suki D, Yang D, Shi W, Aldape K. The natural history of EGFR and EGFRvIII in glioblastoma patients. J Transl Med. 2005;3(1):38.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Heldin CH. Protein tyrosine kinase receptors. Cancer Surv. 1996;27:7–24.PubMedGoogle Scholar
  41. 41.
    Heldin CH, Lennartsson J. Structural and functional properties of platelet-derived growth factor and stem cell factor receptors. Cold Spring Harb Perspect Biol. 2013;5(8):a009100.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hirata A, Hosoi F, Miyagawa M, Ueda S, Naito S, Fujii T, Kuwano M, Ono M. HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells. Cancer Res. 2005;65(10):4253–60.PubMedCrossRefGoogle Scholar
  43. 43.
    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(1):55–7.CrossRefGoogle Scholar
  44. 44.
    Huang PH, Xu AM, White FM. Oncogenic EGFR signaling networks in glioma. Sci Signal. 2009;2(87):re6.PubMedCrossRefGoogle Scholar
  45. 45.
    Huang WJ, Chen WW, Zhang X. Glioblastoma multiforme: effect of hypoxia and hypoxia inducible factors on therapeutic approaches. Oncol Lett. 2016;12(4):2283–8.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Hubbard SR, Till JH: Protein tyrosine kinase structure and function. Annu Rev Biochem. 2000;69:373–98.CrossRefGoogle Scholar
  47. 47.
    Joensuu H, Puputti M, Sihto H, Tynninen O, Nupponen NN: Amplification of genes encoding KIT, PDGFRalpha and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. J Pathol. 2005;207(2):224–31.CrossRefGoogle Scholar
  48. 48.
    Kahn J, Hayman TJ, Jamal M, Rath BH, Kramp T, Camphausen K, Tofilon PJ. The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells. Neuro-oncology. 2014;16(1):29–37.PubMedCrossRefGoogle Scholar
  49. 49.
    Kalpathy-Cramer J, Chandra V, Da X, Ou Y, Emblem KE, Muzikansky A, Cai X, Douw L, Evans JG, Dietrich J, Chi AS, Wen PY, Stufflebeam S, Rosen B, Duda DG, Jain RK, Batchelor TT, Gerstner ER: Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. J Neurooncol. 2017;131(3):603–10.PubMedCrossRefGoogle Scholar
  50. 50.
    Kapoor GS, O’Rourke DM. Mitogenic signaling cascades in glial tumors. Neurosurgery. 2003;52(6):1425–34. (discussion 1434–5).PubMedCrossRefGoogle Scholar
  51. 51.
    Kapoor GS, O’Rourke DM. Receptor tyrosine kinase signaling in gliomagenesis: pathobiology and therapeutic approaches. Cancer Biol Ther. 2003;2(4): 330–42.CrossRefGoogle Scholar
  52. 52.
    Knobbe CB, Reifenberger J, Reifenberger G: Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. Acta Neuropathol. 2004;108(6):467–70.CrossRefGoogle Scholar
  53. 53.
    Knubel KH, Pernu BM, Sufit A, Nelson S, Pierce AM, Keating AK. MerTK inhibition is a novel therapeutic approach for glioblastoma multiforme. Oncotarget. 2014;5(5):1338–51.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med, 2012;2(7):169–183.CrossRefGoogle Scholar
  55. 55.
    Koul D. PTEN signaling pathways in glioblastoma. Cancer Biol Ther. 2008;7(9):1321–5.PubMedCrossRefGoogle Scholar
  56. 56.
    Koul D, Fu J, Shen R, LaFortune TA, Wang S, Tiao N, Kim YW, Liu JL, Ramnarian D, Yuan Y, Garcia-Echevrria C, Maira SM, Yung WK: Antitumor activity of NVP-BKM120–a selective pan class I PI3 kinase inhibitor showed differential forms of cell death based on p53 status of glioma cells. Clin Cancer Res. 2012;18(1):184–95.CrossRefGoogle Scholar
  57. 57.
    Lau CJ, Koty Z, Nalbantoglu J. Differential response of glioma cells to FOXO1-directed therapy. Cancer Res. 2009;69(13):5433–40.PubMedCrossRefGoogle Scholar
  58. 58.
    Lee J, Son MJ, Woolard K, Donin NM, Li A, Cheng CH, Kotliarova S, Kotliarov Y, Walling J, Ahn S, Kim M, Totonchy M, Cusack T, Ene C, Ma H, Su Q, Zenklusen JC, Zhang W, Maric D, Fine HA. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008;13(1):69–80.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275(5308):1943–7.PubMedCrossRefGoogle Scholar
  60. 60.
    Liu P, Cheng H, Roberts TM, Zhao JJ: Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627–44.CrossRefGoogle Scholar
  61. 61.
    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–20.PubMedCrossRefGoogle Scholar
  62. 62.
    Ma DJ, Galanis E, Anderson SK, Schiff D, Kaufmann TJ, Peller PJ, Giannini C, Brown PD, Uhm JH, McGraw S, Jaeckle KA, Flynn PJ, Ligon KL, Buckner JC, Sarkaria JN: A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K. Neuro-oncology. 2015;17(9):1261–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Maher EA, Furnari FB, Bachoo RM, Rowitch DH, Louis DN, Cavenee WK, DePinho RA: Malignant glioma: genetics and biology of a grave matter. Genes Dev. 2001;15(11):1311–33.PubMedCrossRefGoogle Scholar
  64. 64.
    McMahon G. VEGF receptor signaling in tumor angiogenesis. Oncologist. 2000;5(Suppl 1):3–10.PubMedCrossRefGoogle Scholar
  65. 65.
    Montano N, Cenci T, Martini M, D’Alessandris QG, Pelacchi F, Ricci-Vitiani L, Maira G, De Maria R, Larocca LM, Pallini R. Expression of EGFRvIII in glioblastoma: prognostic significance revisited. Neoplasia. 2011;13(12):1113–21.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Mueller W, Nutt CL, Ehrich M, Riemenschneider MJ, von Deimling A, van den Boom D, Louis DN: Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene. 2007;26(4):583–93.CrossRefGoogle Scholar
  67. 67.
    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(21):5079–86.PubMedGoogle Scholar
  68. 68.
    Nakada M, Kita D, Watanabe T, Hayashi Y, Teng L, Pyko IV, Hamada JI. Aberrant signaling pathways in glioma. Cancers (Basel). 2011;3(3):3242–78.CrossRefGoogle Scholar
  69. 69.
    Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME: Molecular targets of glioma invasion. Cell Mol Life Sci. 2007;64(4):458–78.CrossRefGoogle Scholar
  70. 70.
    Nazarenko I, Hede SM, He X, Hedren A, Thompson J, Lindstrom MS, Nister M. PDGF and PDGF receptors in glioma. Upsala J Med Sci. 2012;117(2):99–112.PubMedCrossRefGoogle Scholar
  71. 71.
    Network CGAR. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–8.CrossRefGoogle Scholar
  72. 72.
    Nicholas MK, Lukas RV, Jafri NF, Faoro L, Salgia R. Epidermal growth factor receptor - mediated signal transduction in the development and therapy of gliomas. Clin Cancer Res. 2006;12(24):7261–70.PubMedCrossRefGoogle Scholar
  73. 73.
    Oh T, Ivan ME, Sun MZ, Safaee M, Fakurnejad S, Clark AJ, Sayegh ET, Bloch O, Parsa AT: PI3K pathway inhibitors: potential prospects as adjuncts to vaccine immunotherapy for glioblastoma. Immunotherapy. 2014;6(6): 737–53.CrossRefGoogle Scholar
  74. 74.
    Ondracek J, Fadrus P, Sana J, Besse A, Loja T, Vecera M, Radova L, Smrcka M, Slampa P, Slaby O. Global microRNA expression profiling identifies unique micrioRNA pattern of radioresistant glioblastoma cells. Anticancer Res. 2017;37(3):1099–104.PubMedCrossRefGoogle Scholar
  75. 75.
    Ono M, Kuwano M. Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res. 2006;12(24):7242–51.PubMedCrossRefGoogle Scholar
  76. 76.
    Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol, 2011;3(1 Suppl): S7–S19.Google Scholar
  77. 77.
    Pearson JRD, Regad T. Targeting cellular pathways in glioblastoma multiforme. Signal Transduct Target Ther. 2017;2:17040.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Pelloski CE, Lin E, Zhang L, Yung WK, Colman H, Liu JL, Woo SY, Heimberger AB, Suki D, Prados M, Chang S, Barker FG, Fuller GN, Aldape KD: Prognostic associations of activated mitogen-activated protein kinase and Akt pathways in glioblastoma. Clin Cancer Res. 2006;12(13):3935–41.PubMedCrossRefGoogle Scholar
  79. 79.
    Pierce GF, Mustoe TA, Altrock BW, Deuel TF, Thomason A: Role of platelet-derived growth factor in wound healing. J Cell Biochem. 1991;45(4):319–26.CrossRefGoogle Scholar
  80. 80.
    Pitz MW, Eisenhauer EA, MacNeil MV, Thiessen B, Easaw JC, Macdonald DR, Eisenstat DD, Kakumanu AS, Salim M, Chalchal H, Squire J, Tsao MS, Kamel-Reid S, Banerji S, Tu D, Powers J, Hausman DF, Mason WP: Phase II study of PX-866 in recurrent glioblastoma. Neuro-oncology. 2015;17(9):1270–4.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, Kabuubi P, Ayers-Ringler J, Rabbitt J, Page M, Fedoroff A, Sneed PK, Berger MS, McDermott MW, Parsa AT, Vandenberg S, James CD, Lamborn KR, Stokoe D, Haas-Kogan DA. Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol. 2009;27(4): 579–84.CrossRefGoogle Scholar
  82. 82.
    Qian Z, Ren L, Wu D, Yang X, Zhou Z, Nie Q, Jiang G, Xue S, Weng W, Qiu Y, Lin Y. Overexpression of FoxO3a is associated with glioblastoma progression and predicts poor patient prognosis. Int J Cancer. 2017;140(12):2792–804.PubMedCrossRefGoogle Scholar
  83. 83.
    Rajasekhar VK, Viale A, Socci ND, Wiedmann M, Hu X, Holland EC. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell. 2003;12(4):889–901.PubMedCrossRefGoogle Scholar
  84. 84.
    Reardon DA, Conrad CA, Cloughesy T, Prados MD, Friedman HS, Aldape KD, Mischel P, Xia J, DiLea C, Huang J, Mietlowski W, Dugan M, Chen W, Yung WK. Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients. Cancer Chemother Pharmacol. 2012;69(6):1507–18.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Regad T. Targeting RTK signaling pathways in cancer. Cancers (Basel). 2015;7(3):1758–84.PubMedCentralCrossRefGoogle Scholar
  86. 86.
    Robinson DR, Wu YM, Lin SF. The protein tyrosine kinase family of the human genome. Oncogene. 2000;19(49):5548–57.PubMedCrossRefGoogle Scholar
  87. 87.
    Robinson JP, Vanbrocklin MW, McKinney AJ, Gach HM, Holmen SL. Akt signaling is required for glioblastoma maintenance in vivo. Am J Cancer Res. 2011;1(2):155–67.PubMedGoogle Scholar
  88. 88.
    Shapiro WR, Green SB, Burger PC, Mahaley MS Jr, Selker RG, VanGilder JC, Robertson JT, Ransohoff J, Mealey J Jr, Strike TA. Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma Brain Tumor Cooperative Group Trial 8001. J Neurosurg. 1989;71(1):1–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Shibuya M. Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Struct Funct. 2001;26(1):25–35.PubMedCrossRefGoogle Scholar
  90. 90.
    Shibuya M: Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) Signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2011;2(12):1097–105.CrossRefGoogle Scholar
  91. 91.
    Simpson PB, Armstrong RC. Intracellular signals and cytoskeletal elements involved in oligodendrocyte progenitor migration. Glia. 1999;26(1):22–35.PubMedCrossRefGoogle Scholar
  92. 92.
    Smith JS, Tachibana I, Passe SM, Huntley BK, Borell TJ, Iturria N, O’Fallon JR, Schaefer PL, Scheithauer BW, James CD, Buckner JC, Jenkins RB. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J Natl Cancer Inst. 2001;93(16):1246–56.PubMedCrossRefGoogle Scholar
  93. 93.
    Smrdel U, Popovic M, Zwitter M, Bostjancic E, Zupan A, Kovac V, Glavac D, Bokal D, Jerebic J. Long-term survival in glioblastoma: methyl guanine methyl transferase (MGMT) promoter methylation as independent favourable prognostic factor. Radiol Oncol. 2016;50(4):394–401.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Sonoda Y, Ozawa T, Aldape KD, Deen DF, Berger MS, Pieper RO. Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res. 2001;61(18):6674–8.PubMedGoogle Scholar
  95. 95.
    Stea B, Falsey R, Kislin K, Patel J, Glanzberg H, Carey S, Ambrad AA, Meuillet EJ, Martinez JD. Time and dose-dependent radiosensitization of the glioblastoma multiforme U251 cells by the EGF receptor tyrosine kinase inhibitor ZD1839 (‘Iressa’). Cancer Lett. 2003;202(1):43–51.PubMedCrossRefGoogle Scholar
  96. 96.
    Steiner HH, Karcher S, Mueller MM, Nalbantis E, Kunze S, Herold-Mende C: Autocrine pathways of the vascular endothelial growth factor (VEGF) in glioblastoma multiforme: clinical relevance of radiation-induced increase of VEGF levels. J Neurooncol. 2004;66(1–2):129–38.Google Scholar
  97. 97.
    Stupp R, van den Bent MJ, Hegi ME. Optimal role of temozolomide in the treatment of malignant gliomas. Curr Neurol Neurosci Rep. 2005;5(3):198–206.PubMedCrossRefGoogle Scholar
  98. 98.
    ten Dijke P, Ichijo H, Franzen P, Schulz P, Saras J, Toyoshima H, Heldin CH, Miyazono K. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene. 1993;8(10):2879–87.PubMedGoogle Scholar
  99. 99.
    Thiessen B, Stewart C, Tsao M, Kamel-Reid S, Schaiquevich P, Mason W, Easaw J, Belanger K, Forsyth P, McIntosh L, Eisenhauer E. A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation. Cancer Chemother Pharmacol. 2010;65(2): 353–61.CrossRefGoogle Scholar
  100. 100.
    Thorne AH, Zanca C, Furnari F. Epidermal growth factor receptor targeting and challenges in glioblastoma. Neuro-oncology. 2016;18(7):914–8.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Tiong KH, Mah LY, Leong CO. Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers. Apoptosis. 2013;18(12):1447–68.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, Kleihues P, Ohgaki H. PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol. 1998;57(7):684–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Tufro-McReddie A, Norwood VF, Aylor KW, Botkin SJ, Carey RM, Gomez RA: Oxygen regulates vascular endothelial growth factor-mediated vasculogenesis and tubulogenesis. Dev Biol. 1997;183(2):139–49.CrossRefGoogle Scholar
  104. 104.
    Uhm JH, Ballman KV, Wu W, Giannini C, Krauss JC, Buckner JC, James CD, Scheithauer BW, Behrens RJ, Flynn PJ, Schaefer PL, Dakhill SR, Jaeckle KA. Phase II evaluation of gefitinib in patients with newly diagnosed Grade 4 astrocytoma: Mayo/North Central Cancer Treatment Group Study N0074. Int J Radiat Oncol Biol Phys. 2011;80(2): 347–53.CrossRefGoogle Scholar
  105. 105.
    Vajkoczy P, Knyazev P, Kunkel A, Capelle HH, Behrndt S, von Tengg-Kobligk H, Kiessling F, Eichelsbacher U, Essig M, Read TA, Erber R, Ullrich A. Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci USA, 2006;103(15): 5799–804.CrossRefGoogle Scholar
  106. 106.
    Wang G, Kang C, Pu P. Increased expression of Akt2 and activity of PI3K and cell proliferation with the ascending of tumor grade of human gliomas. Clin Neurol Neurosurg. 2010;112(4):324–7.PubMedCrossRefGoogle Scholar
  107. 107.
    Wang J, Pursell NW, Samson ME, Atoyan R, Ma AW, Selmi A, Xu W, Cai X, Voi M, Savagner P, Lai CJ. Potential advantages of CUDC-101, a multitargeted HDAC, EGFR, and HER2 inhibitor, in treating drug resistance and preventing cancer cell migration and invasion. Mol Cancer Ther. 2013;12(6):925–36.Google Scholar
  108. 108.
    Weathers SP, de Groot J. VEGF manipulation in glioblastoma. Oncology (Williston Park). 2015;29(10):720–7.Google Scholar
  109. 109.
    Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, Vogelstein B. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci USA. 1992;89(7):2965–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Xu K, Zhang Z, Pei H, Wang H, Li L, Xia Q: FoxO3a induces temozolomide resistance in glioblastoma cells via the regulation of beta-catenin nuclear accumulation. Oncol Rep. 2017;37(4):2391–239.CrossRefGoogle Scholar
  111. 111.
    Zwick E, Bange J, Ullrich A: Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer. 2001;8(3):161–73.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medical Genetics, Faculty of MedicineNear East UniversityNicosiaCyprus

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