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EGFR and HER2: Relevance in Renal Cell Carcinoma

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Renal Cell Carcinoma

Abstract

The ErbB family of receptor tyrosine kinases comprises of epidermal growth factor (EGF) receptor (HER1/ErbB1), HER2/neu (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Interaction of ErbB receptors with a ligand leads to formation of higher-order aggregates which may form signaling platforms in the plasma membrane. ErbB2 is the only receptor which doesn’t need a ligand for activation. Various molecules have been developed which block ErbB signaling by either generating antibodies against the extracellular domain of the EGF receptor or directly inhibiting ErbB1/EGF signaling. The relevance of the ErbB family of receptors as actionable targets in renal cell carcinoma is a topic of debate. Some of the recently developed drugs that are discussed in this chapter and have been studied in renal cell carcinoma are cetuximab, panitumumab, gefitinib, erlotinib, and lapatinib. These agents have failed to demonstrate consistent clinical benefit in patients with advanced renal cell carcinoma and are currently not considered standard treatment in this disease.

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References

  1. Bazley LA, Gullick WJ. The epidermal growth factor receptor family. Endocr Relat Cancer. 2005;12 Suppl 1:S17–27.

    CAS  PubMed  Google Scholar 

  2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127–37.

    CAS  PubMed  Google Scholar 

  3. Normanno N, Bianco C, Strizzi L, et al. The ErbB receptors and their ligands in cancer: an overview. Curr Drug Targets. 2005;6(3):243–57.

    CAS  PubMed  Google Scholar 

  4. Tzahar E, Waterman H, Chen X, et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 1996;16(10):5276–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997;16(7):1647–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Cho HS, Mason K, Ramyar KX, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature. 2003;421(6924):756–60.

    CAS  PubMed  Google Scholar 

  7. Lonardo F, Di Marco E, King CR, et al. The normal erbB-2 product is an atypical receptor-like tyrosine kinase with constitutive activity in the absence of ligand. New Biol. 1990;2(11):992–1003.

    CAS  PubMed  Google Scholar 

  8. D’Souza B, Berdichevsky F, Kyprianou N, Taylor-Papadimitriou J. Collagen-induced morphogenesis and expression of the alpha 2-integrin subunit is inhibited in c-erbB2-transfected human mammary epithelial cells. Oncogene. 1993;8(7):1797–806.

    PubMed  Google Scholar 

  9. Samanta A, LeVea CM, Dougall WC, Qian X, Greene MI. Ligand and p185c-neu density govern receptor interactions and tyrosine kinase activation. Proc Natl Acad Sci U S A. 1994;91(5):1711–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Ram TG, Ethier SP. Phosphatidylinositol 3-kinase recruitment by p185erbB-2 and erbB-3 is potently induced by neu differentiation factor/heregulin during mitogenesis and is constitutively elevated in growth factor-independent breast carcinoma cells with c-erbB-2 gene amplification. Cell Growth Differ. 1996;7(5):551–61.

    CAS  PubMed  Google Scholar 

  11. Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem. 1999;274(13):8865–74.

    CAS  PubMed  Google Scholar 

  12. Kim HH, Sierke SL, Koland JG. Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. J Biol Chem. 1994;269(40):24747–55.

    CAS  PubMed  Google Scholar 

  13. Soltoff SP, Carraway III KL, Prigent SA, Gullick WG, Cantley LC. ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol. 1994;14(6):3550–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. 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.

    PubMed Central  PubMed  Google Scholar 

  15. Pawson T. Protein-tyrosine kinases. Getting down to specifics. Nature. 1995;373(6514):477–8.

    CAS  PubMed  Google Scholar 

  16. Pawson T, Scott JD. Signaling through scaffold, anchoring, and adaptor proteins. Science. 1997;278(5346):2075–80.

    CAS  PubMed  Google Scholar 

  17. Yu H, Jove R. The STATs of cancer—new molecular targets come of age. Nat Rev Cancer. 2004;4(2):97–105.

    CAS  PubMed  Google Scholar 

  18. Hise MK, Jacobs SC, Papadimitriou JC, Drachenberg CI. Transforming growth factor-alpha expression in human renal cell carcinoma: TGF-alpha expression in renal cell carcinoma. Urology. 1996;47(1):29–33.

    CAS  PubMed  Google Scholar 

  19. Mydlo JH, Michaeli J, Cordon-Cardo C, Goldenberg AS, Heston WD, Fair WR. Expression of transforming growth factor alpha and epidermal growth factor receptor messenger RNA in neoplastic and nonneoplastic human kidney tissue. Cancer Res. 1989;49(12):3407–11.

    CAS  PubMed  Google Scholar 

  20. Atlas I, Mendelsohn J, Baselga J, Fair WR, Masui H, Kumar R. Growth regulation of human renal carcinoma cells: role of transforming growth factor alpha. Cancer Res. 1992;52(12):3335–9.

    CAS  PubMed  Google Scholar 

  21. Ramp U, Jaquet K, Reinecke P, et al. Functional intactness of stimulatory and inhibitory autocrine loops in human renal carcinoma cell lines of the clear cell type. J Urol. 1997;157(6):2345–50.

    CAS  PubMed  Google Scholar 

  22. Ramp U, Reinecke P, Gabbert HE, Gerharz CD. Differential response to transforming growth factor (TGF)-alpha and fibroblast growth factor (FGF) in human renal cell carcinomas of the clear cell and papillary types. Eur J Cancer. 2000;36(7):932–41.

    CAS  PubMed  Google Scholar 

  23. Uhlman DL, Nguyen P, Manivel JC, et al. Epidermal growth factor receptor and transforming growth factor alpha expression in papillary and nonpapillary renal cell carcinoma: correlation with metastatic behavior and prognosis. Clin Cancer Res. 1995;1(8):913–20.

    CAS  PubMed  Google Scholar 

  24. Petrides PE, Bock S, Bovens J, Hofmann R, Jakse G. Modulation of pro-epidermal growth factor, pro-transforming growth factor alpha and epidermal growth factor receptor gene expression in human renal carcinomas. Cancer Res. 1990;50(13):3934–9.

    CAS  PubMed  Google Scholar 

  25. Lager DJ, Slagel DD, Palechek PL. The expression of epidermal growth factor receptor and transforming growth factor alpha in renal cell carcinoma. Mod Pathol. 1994;7(5):544–8.

    CAS  PubMed  Google Scholar 

  26. Kaelin Jr WG. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002;2(9):673–82.

    CAS  PubMed  Google Scholar 

  27. de Paulsen N, Brychzy A, Fournier MC, et al. Role of transforming growth factor-alpha in von Hippel–Lindau (VHL)(−/−) clear cell renal carcinoma cell proliferation: a possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci U S A. 2001;98(4):1387–92.

    PubMed Central  PubMed  Google Scholar 

  28. Gunaratnam L, Morley M, Franovic A, et al. Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL(−/−) renal cell carcinoma cells. J Biol Chem. 2003;278(45):44966–74.

    CAS  PubMed  Google Scholar 

  29. Kaelin Jr WG. The von Hippel-Lindau tumor suppressor gene and kidney cancer. Clin Cancer Res. 2004;10(18 Pt 2):6290S–5.

    CAS  PubMed  Google Scholar 

  30. Ciardiello F, Caputo R, Bianco R, et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res. 2001;7(5):1459–65.

    CAS  PubMed  Google Scholar 

  31. Gille J, Swerlick RA, Caughman SW. Transforming growth factor-alpha-induced transcriptional activation of the vascular permeability factor (VPF/VEGF) gene requires AP-2-dependent DNA binding and transactivation. EMBO J. 1997;16(4):750–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997;151(6):1523–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Shiurba RA, Eng LF, Vogel H, Lee YL, Horoupian DS, Urich H. Epidermal growth factor receptor in meningiomas is expressed predominantly on endothelial cells. Cancer. 1988;62(10):2139–44.

    CAS  PubMed  Google Scholar 

  34. Freeman MR, Washecka R, Chung LW. Aberrant expression of epidermal growth factor receptor and HER-2 (erbB-2) messenger RNAs in human renal cancers. Cancer Res. 1989;49(22):6221–5.

    CAS  PubMed  Google Scholar 

  35. Weidner U, Peter S, Strohmeyer T, Hussnatter R, Ackermann R, Sies H. Inverse relationship of epidermal growth factor receptor and HER2/neu gene expression in human renal cell carcinoma. Cancer Res. 1990;50(15):4504–9.

    CAS  PubMed  Google Scholar 

  36. Rotter M, Block T, Busch R, Thanner S, Hofler H. Expression of HER-2/neu in renal-cell carcinoma. Correlation with histologic subtypes and differentiation. Int J Cancer. 1992;52(2):213–7.

    CAS  PubMed  Google Scholar 

  37. Herrera GA. C-erb B-2 amplification in cystic renal disease. Kidney Int. 1991;40(3):509–13.

    CAS  PubMed  Google Scholar 

  38. Latif Z, Watters AD, Bartlett JM, Underwood MA, Aitchison M. Gene amplification and overexpression of HER2 in renal cell carcinoma. BJU Int. 2002;89(1):5–9.

    CAS  PubMed  Google Scholar 

  39. Stumm G, Eberwein S, Rostock-Wolf S, et al. Concomitant overexpression of the EGFR and erbB-2 genes in renal cell carcinoma (RCC) is correlated with dedifferentiation and metastasis. Int J Cancer. 1996;69(1):17–22.

    CAS  PubMed  Google Scholar 

  40. Lipponen P, Eskelinen M, Hietala K, Syrjanen K, Gambetta RA. Expression of proliferating cell nuclear antigen (PC10), p53 protein and c-erbB-2 in renal adenocarcinoma. Int J Cancer. 1994;57(2):275–80.

    CAS  PubMed  Google Scholar 

  41. Oya M, Mikami S, Mizuno R, et al. Differential expression of activator protein-2 isoforms in renal cell carcinoma. Urology. 2004;64(1):162–7.

    PubMed  Google Scholar 

  42. Zhang XH, Takenaka I, Sato C, Sakamoto H. p53 and HER-2 alterations in renal cell carcinoma. Urology. 1997;50(4):636–42.

    CAS  PubMed  Google Scholar 

  43. Seliger B, Rongcun Y, Atkins D, et al. HER-2/neu is expressed in human renal cell carcinoma at heterogeneous levels independently of tumor grading and staging and can be recognized by HLA-A2.1-restricted cytotoxic T lymphocytes. Int J Cancer. 2000;87(3):349–59.

    CAS  PubMed  Google Scholar 

  44. Selli C, Amorosi A, Vona G, et al. Retrospective evaluation of c-erbB-2 oncogene amplification using competitive PCR in collecting duct carcinoma of the kidney. J Urol. 1997;158(1):245–7.

    CAS  PubMed  Google Scholar 

  45. Fujimoto E, Yano T, Sato H, et al. Cytotoxic effect of the Her-2/Her-1 inhibitor PKI-166 on renal cancer cells expressing the connexin 32 gene. J Pharmacol Sci. 2005;97(2):294–8.

    CAS  PubMed  Google Scholar 

  46. Gemmill RM, Zhou M, Costa L, Korch C, Bukowski RM, Drabkin HA. Synergistic growth inhibition by Iressa and Rapamycin is modulated by VHL mutations in renal cell carcinoma. Br J Cancer. 2005;92(12):2266–77.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Gill GN, Kawamoto T, Cochet C, et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem. 1984;259(12):7755–60.

    CAS  PubMed  Google Scholar 

  48. Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci U S A. 1983;80(5):1337–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995;1(11):1311–8.

    CAS  PubMed  Google Scholar 

  50. Perera AD, Kleymenova EV, Walker CL. Requirement for the von Hippel Lindau tumor suppressor gene for functional epidermal growth factor receptor blockade by monoclonal antibody C225 in renal cell carcinoma. Clin Cancer Res. 2000;6:1518–23.

    CAS  PubMed  Google Scholar 

  51. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hematol. 2001;38(1):17–23.

    CAS  PubMed  Google Scholar 

  52. Yang XD, Jia XC, Corvalan JR, Wang P, Davis CG, Jakobovits A. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res. 1999;59(6):1236–43.

    CAS  PubMed  Google Scholar 

  53. Foon KA, Yang XD, Weiner LM, et al. Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int J Radiat Oncol Biol Phys. 2004;58(3):984–90.

    CAS  PubMed  Google Scholar 

  54. Wakeling AE, Barker AJ, Davies DH, et al. Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res Treat. 1996;38(1):67–73.

    CAS  PubMed  Google Scholar 

  55. Wakeling AE, Guy SP, Woodburn JR, et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 2002;62(20):5749–54.

    CAS  PubMed  Google Scholar 

  56. Barker AJ, Gibson KH, Grundy W, et al. Studies leading to the identification of ZD1839 (IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett. 2001;11(14):1911–4.

    CAS  PubMed  Google Scholar 

  57. Sumitomo M, Asano T, Asakuma J, Asano T, Horiguchi A, Hayakawa M. ZD1839 modulates paclitaxel response in renal cancer by blocking paclitaxel-induced activation of the epidermal growth factor receptor-extracellular signal-regulated kinase pathway. Clin Cancer Res. 2004;10(2):794–801.

    CAS  PubMed  Google Scholar 

  58. Moyer JD, Barbacci EG, Iwata KK, et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. 1997;57(21):4838–48.

    CAS  PubMed  Google Scholar 

  59. Pollack VA, Savage DM, Baker DA, et al. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J Pharmacol Exp Ther. 1999;291(2):739–48.

    CAS  PubMed  Google Scholar 

  60. Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem. 2002;277(48):46265–72.

    CAS  PubMed  Google Scholar 

  61. Rusnak DW, Lackey K, Affleck K, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther. 2001;1(2):85–94.

    CAS  PubMed  Google Scholar 

  62. Rusnak DW, Affleck K, Cockerill SG, et al. The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res. 2001;61(19):7196–203.

    CAS  PubMed  Google Scholar 

  63. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1):289–96.

    CAS  PubMed  Google Scholar 

  64. Hainsworth JD, Sosman JA, Spigel DR, Edwards DL, Baughman C, Greco A. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol. 2005;23(31):7889–96.

    CAS  PubMed  Google Scholar 

  65. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–34.

    CAS  PubMed  Google Scholar 

  66. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24.

    CAS  PubMed  Google Scholar 

  67. Rowinsky EK, Schwartz GH, Gollob JA, et al. Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol. 2004;22(15):3003–15.

    CAS  PubMed  Google Scholar 

  68. Druker BJ, Schwartz L, Marion S, Motzer RJ. Phase II trial of ZD 1839 (Iressa), and EGF receptor inhibitor, in patients with renal cell carcinoma. In: Proc Am Soc Clin Oncol; 2002. p. 720 [George D, 2001 #150].

    Google Scholar 

  69. Dawson NA, Guo C, Zak R, et al. A phase II trial of gefitinib (Iressa, ZD1839) in stage IV and recurrent renal cell carcinoma. Clin Cancer Res. 2004;10(23):7812–9.

    CAS  PubMed  Google Scholar 

  70. Jermann M, Stahel RA, Salzberg M, et al. A phase II, open-label study of gefitinib (IRESSA) in patients with locally advanced, metastatic, or relapsed renal-cell carcinoma. Cancer Chemother Pharmacol. 2005;57:533–9.

    PubMed  Google Scholar 

  71. Motzer RJ, Hudes GR, Ginsberg MS, et al. Phase I/II trial of sunitinib plus gefitinib in patients with metastatic renal cell carcinoma. Am J Clin Oncol. 2010;33(6):614–8.

    CAS  PubMed  Google Scholar 

  72. Shek D, Longmate J, Quinn DI, et al. A phase II trial of gefitinib and pegylated IFNα in previously treated renal cell carcinoma. Int J Clin Oncol. 2011;16(5):494–9.

    CAS  PubMed  Google Scholar 

  73. Bukowski RM, Kabbinavar F, Figlin RA, et al. Bevacizumab with or without erlotinib in metastatic renal cell carcinoma (RCC). In: ASCO; 2006. p. 4523.

    Google Scholar 

  74. Gordon MS, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009;27(34):5788–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Flaig TW, Costa LJ, Gustafson DL, et al. Safety and efficacy of the combination of erlotinib and sirolimus for the treatment of metastatic renal cell carcinoma after failure of sunitinib or sorafenib. Br J Cancer. 2010;103(6):796–801.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Ravaud A, Gardner J, Hawkins R, et al. Efficacy of lapatinib in patients with high tumor EGFR expression: results of a phase III trial in advanced renal cell carcinoma (RCC). In: ASCO; 2006. p. 4502.

    Google Scholar 

  77. Weinstein IB, Joe AK. Mechanisms of disease: oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. 2006;3(8):448–57.

    CAS  PubMed  Google Scholar 

  78. Weinstein IB. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science. 2002;297(5578):63–4.

    CAS  PubMed  Google Scholar 

  79. Engelman JA, Janne PA, Mermel C, et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci U S A. 2005;102(10):3788–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Hahn WC, Weinberg RA. Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2002;2(5):331–41.

    CAS  PubMed  Google Scholar 

  81. Smith K, Gunaratnam L, Morley M, Franovic A, Mekhail K, Lee S. Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL−/− renal cancer. Cancer Res. 2005;65(12):5221–30.

    CAS  PubMed  Google Scholar 

  82. Kim HL, Seligson D, Liu X, et al. Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma. J Urol. 2005;173(5):1496–501.

    CAS  PubMed  Google Scholar 

  83. Kim HL, Seligson D, Liu X, et al. Using protein expressions to predict survival in clear cell renal carcinoma. Clin Cancer Res. 2004;10(16):5464–71.

    CAS  PubMed  Google Scholar 

  84. Kondo K, Yao M, Kobayashi K, et al. PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. Int J Cancer. 2001;91(2):219–24.

    CAS  PubMed  Google Scholar 

  85. Brenner W, Farber G, Herget T, Lehr HA, Hengstler JG, Thuroff JW. Loss of tumor suppressor protein PTEN during renal carcinogenesis. Int J Cancer. 2002;99(1):53–7.

    CAS  PubMed  Google Scholar 

  86. Sulis ML, Parsons R. PTEN: from pathology to biology. Trends Cell Biol. 2003;13(9):478–83.

    CAS  PubMed  Google Scholar 

  87. Eng C. PTEN: one gene, many syndromes. Hum Mutat. 2003;22(3):183–98.

    CAS  PubMed  Google Scholar 

  88. Leslie NR, Downes CP. PTEN: the down side of PI 3-kinase signalling. Cell Signal. 2002;14(4):285–95.

    CAS  PubMed  Google Scholar 

  89. Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 2006;6(3):184–92.

    CAS  PubMed  Google Scholar 

  90. Bianco R, Shin I, Ritter CA, 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(18):2812–22.

    CAS  PubMed  Google Scholar 

  91. Velickovic M, Delahunt B, McIver B, Grebe SK. Intragenic PTEN/MMAC1 loss of heterozygosity in conventional (clear-cell) renal cell carcinoma is associated with poor patient prognosis. Mod Pathol. 2002;15(5):479–85.

    PubMed  Google Scholar 

  92. Hara S, Oya M, Mizuno R, Horiguchi A, Marumo K, Murai M. Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor. Ann Oncol. 2005;16(6):928–33.

    CAS  PubMed  Google Scholar 

  93. Goldman CK, Kim J, Wong WL, King V, Brock T, Gillespie GY. Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Mol Biol Cell. 1993;4(1):121–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. O-charoenrat P, Rhys-Evans P, Modjtahedi H, Eccles SA. Vascular endothelial growth factor family members are differentially regulated by c-erbB signaling in head and neck squamous carcinoma cells. Clin Exp Metastasis. 2000;18(2):155–61.

    CAS  PubMed  Google Scholar 

  95. Ravindranath N, Wion D, Brachet P, Djakiew D. Epidermal growth factor modulates the expression of vascular endothelial growth factor in the human prostate. J Androl. 2001;22(3):432–43.

    CAS  PubMed  Google Scholar 

  96. Baker CH, Kedar D, McCarty MF, et al. Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial cells for therapy of human carcinomas. Am J Pathol. 2002;161(3):929–38.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Kedar D, Baker CH, Killion JJ, Dinney CP, Fidler IJ. Blockade of the epidermal growth factor receptor signaling inhibits angiogenesis leading to regression of human renal cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 2002;8(11):3592–600.

    CAS  PubMed  Google Scholar 

  98. Baker CH, Pino MS, Fidler IJ. Phosphorylated epidermal growth factor receptor on tumor-associated endothelial cells in human renal cell carcinoma is a primary target for therapy by tyrosine kinase inhibitors. Neoplasia. 2006;8(6):470–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Weber KL, Doucet M, Price JE, Baker C, Kim SJ, Fidler IJ. Blockade of epidermal growth factor receptor signaling leads to inhibition of renal cell carcinoma growth in the bone of nude mice. Cancer Res. 2003;63(11):2940–7.

    CAS  PubMed  Google Scholar 

  100. Viloria-Petit A, Crombet T, Jothy S, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 2001;61(13):5090–101.

    CAS  PubMed  Google Scholar 

  101. Ciardiello F, Caputo R, Damiano V, et al. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res. 2003;9(4):1546–56.

    CAS  PubMed  Google Scholar 

  102. Bell DW, Lynch TJ, Haserlat SM, et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005;23(31):8081–92.

    CAS  PubMed  Google Scholar 

  103. Perez-Soler R, Chachoua A, Hammond LA, et al. Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. J Clin Oncol. 2004;22(16):3238–47.

    CAS  PubMed  Google Scholar 

  104. Parra HS, Cavina R, Latteri F, et al. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib (‘Iressa’, ZD1839) in non-small-cell lung cancer. Br J Cancer. 2004;91(2):208–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Gordon AN, Finkler N, Edwards RP, et al. Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. Int J Gynecol Cancer. 2005;15(5):785–92.

    CAS  PubMed  Google Scholar 

  106. Sirotnak FM, Zakowski MF, Miller VA, Scher HI, Kris MG. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res. 2000;6(12):4885–92.

    CAS  PubMed  Google Scholar 

  107. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol. 2005;23(11):2445–59.

    CAS  PubMed  Google Scholar 

  108. Rojo F, Tabernero J, Albanell J, et al. Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma. J Clin Oncol. 2006;24(26):4309–16.

    CAS  PubMed  Google Scholar 

  109. Giaccone G. HER1/EGFR-targeted agents: predicting the future for patients with unpredictable outcomes to therapy. Ann Oncol. 2005;16(4):538–48.

    CAS  PubMed  Google Scholar 

  110. Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol. 2005;23(11):2556–68.

    CAS  PubMed  Google Scholar 

  111. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129–39.

    CAS  PubMed  Google Scholar 

  112. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497–500.

    CAS  PubMed  Google Scholar 

  114. Tsuchihashi Z, Khambata-Ford S, Hanna N, Janne PA. Responsiveness to cetuximab without mutations in EGFR. N Engl J Med. 2005;353(2):208–9.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX, 77030, USA

    Sarathi Kalra M.D. & Eric Jonasch M.D.

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  1. Sarathi Kalra M.D.
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  2. Eric Jonasch M.D.
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Correspondence to Eric Jonasch M.D. .

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Editors and Affiliations

  1. Taussig Cancer Center, Cleveland Clinic, Pepper Pike, Ohio, USA

    Ronald M. Bukowski

  2. Division of Hematology Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Robert A. Figlin

  3. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Robert J. Motzer

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Kalra, S., Jonasch, E. (2015). EGFR and HER2: Relevance in Renal Cell Carcinoma. In: Bukowski, R., Figlin, R., Motzer, R. (eds) Renal Cell Carcinoma. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1622-1_14

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  • DOI: https://doi.org/10.1007/978-1-4939-1622-1_14

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