Molecular Oncology
Volume 1, Issue 1 , Pages 42-54 , June 2007

Cancer therapeutic antibodies come of age: Targeting minimal residual disease

  • Tsipi Ben-Kasus

      Affiliations

    • Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
  • ,
  • Bilha Schechter

      Affiliations

    • Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
  • ,
  • Michael Sela

      Affiliations

    • Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
  • ,
  • Yosef Yarden

      Affiliations

    • Department of Biological Regulation, The Feinberg Graduate School, The Weizmann Institute of Science, Room 302, Rehovot 76100, Israel
    • Corresponding Author InformationCorresponding author. Tel.: +972 8 9343974; Fax: +972 8 9342488.

Received 18 January 2007 ,Accepted 24 January 2007.

References 

  1. Aboud-Pirak E, Hurwitz E, Pirak ME, Bellot F, Schlessinger J, Sela M. Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. J. Natl. Cancer Inst. 1988;80:1605–1611
  2. Andrechek ER, Muller WJ. Tyrosine kinase signalling in breast cancer: tyrosine kinase-mediated signal transduction in transgenic mouse models of human breast cancer. Breast Cancer Res. 2000;2:211–216
  3. Austin CD, De Maziere AM, Pisacane PI, van Dijk SM, Eigenbrot C, Sliwkowski MX, et al. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. Mol. Biol. Cell. 2004;15:5268–5282
  4. Balzar M, Winter MJ, de Boer CJ, Litvinov SV. The biology of the 17-1A antigen (Ep-CAM). J Mol. Med. 1999;77:699–712
  5. Bargmann CI, Hung MC, Weinberg RA. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell. 1986;45:649–657
  6. Baselga J, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J. Clin. Oncol. 1996;14:737–744
  7. Baselga J, Perez EA, Pienkowski T, Bell R. Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer. Oncologist. 2006;11(Suppl. 1):4–12
  8. Beerli RR, Wels W, Hynes NE. Intracellular expression of single chain antibodies reverts ErbB-2 transformation. J. Biol. Chem. 1994;269:23931–23936
  9. Bell R. What can we learn from Herceptin trials in metastatic breast cancer?. Oncology. 2002;63:39–46
  10. Bezombes C, Grazide S, Garret C, Fabre C, Quillet-Mary A, Muller S, et al. Rituximab antiproliferative effect in B-lymphoma cells is associated with acid-sphingomyelinase activation in raft microdomains. Blood. 2004;104:1166–1173
  11. Bober LA, Grace MJ, Pugliese-Sivo C, Rojas-Triana A, Waters T, Sullivan LM, et al. The effect of GM-CSF and G-CSF on human neutrophil function. Immunopharmacology. 1995;29:111–119
  12. Bonavida B, Vega MI. Rituximab-mediated chemosensitization of AIDS and non-AIDS non-Hodgkin's lymphoma. Drug Resist. Updat. 2005;8:27–41
  13. Bonner JA, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 2006;354:567–578
  14. Boulianne GL, Hozumi N, Shulman MJ. Production of functional chimaeric mouse/human antibody. Nature. 1984;312:643–646
  15. Bubien JK, Zhou LJ, Bell PD, Frizzell RA, Tedder TF. Transfection of the CD20 cell surface molecule into ectopic cell types generates a Ca2+ conductance found constitutively in B lymphocytes. J. Cell Biol. 1993;121:1121–1132
  16. Carnahan J, Stein R, Qu Z, Hess K, Cesano A, Hansen HJ, et al. Epratuzumab, a CD22-targeting recombinant humanized antibody with a different mode of action from rituximab. Mol. Immunol. 2007;44:1331–1341
  17. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002;99:754–758
  18. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature. 2003;421:756–760
  19. Christianson TA, Doherty JK, Lin YJ, Ramsey EE, Holmes R, Keenan EJ, et al. NH2-terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer. Cancer Res. 1998;58:5123–5129
  20. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat. Rev. Mol. Cell Biol. 2006;7:505–516
  21. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat. Med. 2000;6:443–446
  22. Cobleigh MA, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 1999;17:2639–2648
  23. Cragg MS, Walshe CA, Ivanov AO, Glennie MJ. The biology of CD20 and its potential as a target for mAb therapy. Curr. Dir. Autoimmun. 2005;8:140–174
  24. Cuello M, Ettenberg SA, Clark AS, Keane MM, Posner RH, Nau MM, et al. Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res. 2001;61:4892–4900
  25. Deans JP, Li H, Polyak MJ. CD20-mediated apoptosis: signalling through lipid rafts. Immunology. 2002;107:176–182
  26. Di Gaetano N, et al. Complement activation determines the therapeutic activity of rituximab in vivo. J. Immunol. 2003;171:1581–1587
  27. Dijoseph JF, Dougher MM, Armellino DC, Kalyandrug L, Kunz A, Boghaert ER, et al. CD20-specific antibody-targeted chemotherapy of non-Hodgkin's B-cell lymphoma using calicheamicin-conjugated rituximab. Cancer Immunol. Immunother. 2006;[Epub ahead of print]
  28. Drebin JA, Link VC, Weinberg RA, Greene MI. Inhibition of tumor growth by a monoclonal antibody reactive with an oncogene-encoded tumor antigen. Proc. Natl. Acad. Sci. U. S. A. 1986;83:9129–9133
  29. Erickson SL, O'Shea KS, Ghaboosi N, Loverro L, Frantz G, Bauer M, et al. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice. Development. 1997;124:4999–5011
  30. Ferrara N. VEGF as a therapeutic target in cancer. Oncology. 2005;69(Suppl. 3):11–16
  31. Fishwild DM, et al. High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat. Biotechnol. 1996;14:845–851
  32. Flanagan JG, Leder P. neu proto-oncogene fused to an immunoglobulin heavy chain gene requires immunoglobulin light chain for cell surface expression and oncogenic transformation. Proc. Natl. Acad. Sci. U. S. A. 1988;85:8057–8061
  33. Friedman LM, Rinon A, Schechter B, Lyass L, Lavi S, Bacus SS, et al. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. Proc. Natl. Acad. Sci. U. S. A. 2005;102:1915–1920
  34. Garrett TP, et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cells. 2003;11:495–505
  35. Gassmann M, Casagranda F, Orioli D, Simon H, Lai C, Klein R, et al. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature. 1995;378:390–394
  36. Gill GN, Kawamoto T, Cochet C, Le A, Sato JD, Masui H, 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;259:7755–7760
  37. Golay J, Lazzari M, Facchinetti V, Bernasconi S, Borleri G, Barbui T, et al. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood. 2001;98:3383–3389
  38. Griffiths AD, et al. Human anti-self antibodies with high specificity from phage display libraries. Embo. J. 1993;12:725–734
  39. Harris NL, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84:1361–1392
  40. Hofmeister JK, Cooney D, Coggeshall KM. Clustered CD20 induced apoptosis: src-family kinase, the proximal regulator of tyrosine phosphorylation, calcium influx, and caspase 3-dependent apoptosis. Blood Cells Mol. Dis. 2000;26:133–143
  41. Hong F, et al. Mechanism by which orally administered beta-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models. J. Immunol. 2004;173:797–806
  42. Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 1999;59:1935–1940
  43. Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol. Cell Biol. 1989;9:1165–1172
  44. Hurwitz E, Stancovski I, Sela M, Yarden Y. Suppression and promotion of tumor growth by monoclonal antibodies to ErbB-2 differentially correlate with cellular uptake. Proc. Nat. Acad. Sci. U. S. A. 1995;92:3353–3357
  45. Iannello A, Ahmad A. Role of antibody-dependent cell-mediated cytotoxicity in the efficacy of therapeutic anti-cancer monoclonal antibodies. Cancer Metastasis Rev. 2005;24:487–499
  46. Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature. 2002;416:279–280
  47. Janas E, Priest R, Wilde JI, White JH, Malhotra R. Rituxan (anti-CD20 antibody)-induced translocation of CD20 into lipid rafts is crucial for calcium influx and apoptosis. Clin. Exp. Immunol. 2005;139:439–446
  48. Joensuu H, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N. Engl. J. Med. 2006;354:809–820
  49. Klapper LN, Glathe S, Vaisman N, Hynes NE, Andrews GC, Sela M, et al. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc. Natl. Acad. Sci. U. S. A. 1999;96:4995–5000
  50. Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975;256:495–497
  51. Konecny G, et al. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer. J. Natl. Cancer Inst. 2003;95:142–153
  52. Lane HA, Motoyama AB, Beuvink I, Hynes NE. Modulation of p27/Cdk2 complex formation through 4D5-mediated inhibition of HER2 receptor signaling. Ann. Oncol. 2001;12:S21–S22
  53. Lopes de Menezes DE, et al. Recombinant interleukin-2 significantly augments activity of rituximab in human tumor xenograft models of B-cell non-Hodgkin lymphoma. J. Immunother. 2007;30:64–74
  54. Lu D, Shen J, Vil MD, Zhang H, Jimenez X, Bohlen P, et al. Tailoring in vitro selection for a picomolar affinity human antibody directed against vascular endothelial growth factor receptor 2 for enhanced neutralizing activity. J. Biol. Chem. 2003;278:43496–43507
  55. Maier LA, Xu FJ, Hester S, Boyer CM, McKenzie S, Bruskin AM, et al. Requirements for the internalization of a murine monoclonal antibody directed against the HER-2/neu gene product c-erbB-2. Cancer Res. 1991;51:5361–5369
  56. Marches R, Uhr JW. Enhancement of the p27Kip1-mediated antiproliferative effect of trastuzumab (Herceptin) on HER2-overexpressing tumor cells. Int. J. Cancer. 2004;112:492–501
  57. Marks JD, Hoogenboom HR, Bonnert TP, McCafferty J, Griffiths AD, Winter G. By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 1991;222:581–597
  58. Marmor MD, Yarden Y. Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene. 2004;23:2057–2070
  59. Mass R. The role of HER-2 expression in predicting response to therapy in breast cancer. Semin. Oncol. 2000;27:46–52(discussion, pp. 92–100)
  60. McKenzie SJ, Marks PJ, Lam T, Morgan J, Panicali DL, Trimpe KL, et al. Generation and characterization of monoclonal antibodies specific for the human neu oncogene product, p185. Oncogene. 1989;4:543–548
  61. McLaughlin P, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J. Clin. Oncol. 1998;16:2825–2833
  62. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000;19:6550–6565
  63. Mendez MJ, et al. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat. Genet. 1997;15:146–156
  64. Modak S, Koehne G, Vickers A, O'Reilly RJ, Cheung NK. Rituximab therapy of lymphoma is enhanced by orally administered (1–>3),(1–>4)-d-beta-glucan. Leuk. Res. 2005;29:679–683
  65. Mohsin SK, et al. Neoadjuvant trastuzumab induces apoptosis in primary breast cancers. J. Clin. Oncol. 2005;23:2460–2468
  66. Molina MA, Codony-Servat J, Albanell J, Rojo F, Arribas J, Baselga J. Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res. 2001;61:4744–4749
  67. Morrison SL, Johnson MJ, Herzenberg LA, Oi VT. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc. Natl. Acad. Sci. U. S. A. 1984;81:6851–6855
  68. Nagata Y, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117–127
  69. Neve RM, Nielsen UB, Kirpotin DB, Poul MA, Marks JD, Benz CC. Biological effects of anti-ErbB2 single chain antibodies selected for internalizing function. Biochem. Biophys. Res. Commun. 2001;280:274–279
  70. Nicholson KM, Streuli CH, Anderson NG. Autocrine signalling through erbB receptors promotes constitutive activation of protein kinase B/Akt in breast cancer cell lines. Breast Cancer Res. Treat. 2003;81:117–128
  71. Nimmerjahn F, Bruhns P, Horiuchi K, Ravetch JV. FcgammaRIV: a novel FcR with distinct IgG subclass specificity. Immunity. 2005;23:41–51
  72. O'Keefe TL, Williams GT, Davies SL, Neuberger MS. Mice carrying a CD20 gene disruption. Immunogenetics. 1998;48:125–132
  73. Olivieri A, et al. A new schedule of CHOP/rituximab plus granulocyte-macrophage colony-stimulating factor is an effective rescue for patients with aggressive lymphoma failing autologous stem cell transplantation. Biol. Blood Marrow Transplant. 2005;11:627–636
  74. Pedersen IM, Buhl AM, Klausen P, Geisler CH, Jurlander J. The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism. Blood. 2002;99:1314–1319
  75. Pegram M, et al. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene. 1999;18:2241–2251
  76. Pegram MD, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol. 1998;16:2659–26710732–183x
  77. Peng D, Fan Z, Lu Y, DeBlasio T, Scher H, Mendelsohn J. Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145. Cancer Res. 1996;56:3666–3669
  78. Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, 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;151:1523–1530
  79. Piccart-Gebhart MJ, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 2005;353:1659–1672
  80. Polyak MJ, Deans JP. Alanine-170 and proline-172 are critical determinants for extracellular CD20 epitopes; heterogeneity in the fine specificity of CD20 monoclonal antibodies is defined by additional requirements imposed by both amino acid sequence and quaternary structure. Blood. 2002;99:3256–3562
  81. Polyak MJ, Tailor SH, Deans JP. Identification of a cytoplasmic region of CD20 required for its redistribution to a detergent-insoluble membrane compartment. J. Immunol. 1998;161:3242–3248
  82. Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57:4593–4599
  83. Pulczynski S, Boesen AM, Jensen OM. Modulation and intracellular transport of CD20 and CD21 antigens induced by B1 and B2 monoclonal antibodies in RAJI and JOK-1 cells – an immunofluorescence and immunoelectron microscopy study. Leuk. Res. 1994;18:541–552
  84. Ravetch JV, Lanier LL. Immune inhibitory receptors. Science. 2000;290:84–89
  85. Riechmann L, Clark M, Waldmann H, Winter G. Reshaping human antibodies for therapy. Nature. 1988;332:323–327
  86. Riethmacher D, Sonnenberg-Riethmacher E, Brinkmann V, Yamaai T, Lewin GR, Birchmeier C. Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature. 1997;389:725–730
  87. Romond EH, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 2005;353:1673–1684
  88. Ross JS, et al. The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy. Oncologist. 2003;8:307–325
  89. Saaristo A, Karpanen T, Alitalo K. Mechanisms of angiogenesis and their use in the inhibition of tumor growth and metastasis. Oncogene. 2000;19:6122–6129
  90. Skvortsova I, Skvortsov S, Popper BA, Haidenberger A, Saurer M, Gunkel AR, et al. Rituximab enhances radiation-triggered apoptosis in non-Hodgkin's lymphoma cells via caspase-dependent and -independent mechanisms. J. Radiat. Res. (Tokyo). 2006;47:183–196
  91. Slamon DJ, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–712
  92. Slamon DJ, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 2001;344:783–792
  93. Slamon D, Eiermann W, Robert N, et al. Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2 positive early breast cancer patients: BCIRG 006 study. Breast Cancer Res. Treat. 2005;94(Suppl. 1):S5
  94. Spiridon CI, Ghetie MA, Uhr J, Marches R, Li JL, Shen GL, et al. Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo. Clin. Cancer. Res. 2002;8:1720–1730
  95. Spiridon CI, Guinn S, Vitetta ES. A comparison of the in vitro and in vivo activities of IgG and F(ab′)2 fragments of a mixture of three monoclonal anti-Her-2 antibodies. Clin. Cancer Res. 2004;10:3542–3551
  96. Stancovski I, Hurwitz E, Leitner O, Ullrich A, Yarden Y, Sela M. Mechanistic aspects of the opposing effects of monoclonal antibodies to the ERBB2 receptor on tumor growth. Proc. Natl. Acad. Sci. U. S. A. 1991;88:8691–8695
  97. Stein R, Belisle E, Hansen HJ, Goldenberg DM. Epitope specificity of the anti-(B cell lymphoma) monoclonal antibody, LL2. Cancer Immunol. Immunother. 1993;37:293–298
  98. Sulis ML, Parsons R. PTEN: from pathology to biology. Trends Cell Biol. 2003;13:478–483
  99. Tuscano JM, O'Donnell RT, Miers LA, Kroger LA, Kukis DL, Lamborn KR, et al. Anti-CD22 ligand-blocking antibody HB22.7 has independent lymphomacidal properties and augments the efficacy of 90Y-DOTA-peptide-Lym-1 in lymphoma xenografts. Blood. 2003;101:3641–3647
  100. Valabrega G, et al. TGFalpha expression impairs Trastuzumab-induced HER2 downregulation. Oncogene. 2005;24:3002–3010
  101. van Meerten T, van Rijn RS, Hol S, Hagenbeek A, Ebeling SB. Complement-induced cell death by rituximab depends on CD20 expression level and acts complementary to antibody-dependent cellular cytotoxicity. Clin. Cancer Res. 2006;12:4027–4035
  102. Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Fisher RI. Long-term update of a phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. Leuk. Lymphoma. 2005;46:1569–1573
  103. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol. 2003;21:3940–3947
  104. 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;59:1236–1243
  105. Yarden Y. Agonistic antibodies stimulate the kinase encoded by the neu protooncogene in living cells but the oncogenic mutant is constitutively active. Proc. Natl. Acad. Sci. U. S. A. 1990;87:2569–2573

PII: S1574-7891(07)00009-9

doi: 10.1016/j.molonc.2007.01.003

Molecular Oncology
Volume 1, Issue 1 , Pages 42-54 , June 2007