Signal Transduction Pathways as Therapeutic Targets in Cancer Therapy

  • Michele MilellaEmail author
  • Ludovica Ciuffreda
  • Emilio Bria
Part of the Macromolecular Anticancer Therapeutics book series (CDD&D)


Cancer is increasingly recognized as “miscommunication” disease, in which inter- and intracellular signals are aberrantly sent and/or received, resulting in the uncontrolled proliferation, survival, and invasiveness of the cancer cell. Indeed, many of the genetic and epigenetic aberrations, which underlie the process of neoplastic transformation and progression, ultimately impinge on the inappropriate activation/inactivation of intracellular signaling pathways. Such signaling cascades usually proceed from the cell surface, where growth factors interact with their specific receptors, to cytoplasmic signaling intermediates, where different signals are integrated and both positive and negative feedback circuitry are in place to ensure signal fidelity and transduction accuracy, to nuclear transcription factors/complexes, which ultimately lead to the transcription/translation of effector genes and proteins involved in specific cellular functions. While the signal may be inappropriately transduced at several, and usually multiple, levels, one interesting feature of aberrant cancer signaling is that cancer cells may become “addicted” to specific signals and hence exquisitely sensitive to their modulation. In this chapter we will describe the signaling process, highlighting the steps at which aberrant signal transduction may turn a normal cell into a cancer cell and the crucial points where aberrant signals can be modulated for therapeutic purposes. Finally, we will briefly touch upon relevant issues surrounding the clinical development of signal transduction inhibitors as anticancer agents.


Epidermal Growth Factor Receptor Chronic Myelogenous Leukemia Epidermal Growth Factor Receptor Mutation Tuberous Sclerosis Complex PIK3CA Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



acute lymphocytic leukemia


acute myeloid leukemia


AMP-activated protein kinase


apoptosis signal kinase 1


adenosine triphosphate


best supportive care


cyclin-dependent kinase(s)


cardio-facio-cutaneous syndrome


chronic myelogenous leukemia


eukaryotic translation initiation factor 4E binding protein 1


epidermal growth factor receptor


extracellular-signal-regulated kinase


fluorescence in situ hybridization


Fms-like tyrosine kinase 3


gastrointestinal stromal tumor(s)


glycogen synthase kinase 3


heat-shock protein


Insulin receptor substrate


Jun N-terminal kinase




mitogen-activated protein kinase


MAPK and ERK kinase


microphthalmia transcription factor


mammalian sterile 20-like kinase


mammalian target of rapamycin (complex)


neurofibromatosis 1


non-small cell lung cancer


platelet-derived growth factor


3-phosphoinositide-dependent protein kinase 1


pleckstrin homology domain


phosphoinositide 3-kinase


AKT (phosphatidylinositol-3 kinase–AKT)


phosphatase and tensin homolog deleted on chromosome 10


regulatory-associated protein of mTOR


(mitogen-activated and extracellular-signal-regulated kinase kinase)


Ras homolog enriched in brain


rapamycin-insensitive companion of mTOR


RNA interference


reactive oxygen species


receptor tyrosine kinase(s)


ribosomal S6 kinase 1


small cell lung cancer


signal transducer and activator of transcription


therapy-induced AML


transforming growth factor a


protein tyrosine kinase(s)


tyrosine kinase inhibitor(s)


tumor necrosis factor


tuberous sclerosis complex


  1. 1.
    Bishop JM (1991) Molecular themes in oncogenesis. Cell 64:235–248PubMedCrossRefGoogle Scholar
  2. 2.
    Hahn WC, Weinberg RA (2002) Rules for making human tumor cells. N Engl J Med 347:1593–1603PubMedCrossRefGoogle Scholar
  3. 3.
    Hahn WC, Weinberg RA (2002) Modelling the molecular circuitry of cancer. Nat Rev Cancer 2:331–341PubMedCrossRefGoogle Scholar
  4. 4.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedCrossRefGoogle Scholar
  5. 5.
    Rowley JD (2008) Chromosomal translocations: revisited yet again. Blood 112:2183–2189PubMedCrossRefGoogle Scholar
  6. 6.
    Cahill DP, Kinzler KW, Vogelstein B, et al. (1999) Genetic instability and darwinian selection in tumours. Trends Cell Biol 9:M57–M60PubMedCrossRefGoogle Scholar
  7. 7.
    Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396:643–649PubMedCrossRefGoogle Scholar
  8. 8.
    Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079PubMedGoogle Scholar
  9. 9.
    Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6:107–116PubMedCrossRefGoogle Scholar
  10. 10.
    Gronbaek K, Hother C, Jones PA (2007) Epigenetic changes in cancer. APMIS 115:1039–1059PubMedCrossRefGoogle Scholar
  11. 11.
    Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349:2042–2054PubMedCrossRefGoogle Scholar
  12. 12.
    Jones PA, Laird PW (1999) Cancer epigenetics comes of age. Nat Genet 21:163–167PubMedCrossRefGoogle Scholar
  13. 13.
    Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428PubMedCrossRefGoogle Scholar
  14. 14.
    Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7:21–33PubMedCrossRefGoogle Scholar
  15. 15.
    Hake SB, Xiao A, Allis CD (2004) Linking the epigenetic “language” of covalent histone modifications to cancer. Br J Cancer 90:761–769PubMedCrossRefGoogle Scholar
  16. 16.
    Lachner M, O’Sullivan RJ, Jenuwein T (2003) An epigenetic road map for histone lysine methylation. J Cell Sci 116:2117–2124PubMedCrossRefGoogle Scholar
  17. 17.
    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45PubMedCrossRefGoogle Scholar
  18. 18.
    Ting AH, McGarvey KM, Baylin SB (2006) The cancer epigenome – components and functional correlates. Genes Dev 20:3215–3231PubMedCrossRefGoogle Scholar
  19. 19.
    Allen A (2007) Epigenetic alterations and cancer: new targets for therapy. IDrugs 10:709–712PubMedGoogle Scholar
  20. 20.
    Gal-Yam EN, Saito Y, Egger G, et al. (2008) Cancer epigenetics: modifications, screening, and therapy. Annu Rev Med 59:267–280PubMedCrossRefGoogle Scholar
  21. 21.
    Smith LT, Otterson GA, Plass C (2007) Unraveling the epigenetic code of cancer for therapy. Trends Genet 23:449–456PubMedCrossRefGoogle Scholar
  22. 22.
    Yoo CB, Jones PA (2006) Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 5:37–50PubMedCrossRefGoogle Scholar
  23. 23.
    Bianco R, Melisi D, Ciardiello F, et al. (2006) Key cancer cell signal transduction pathways as therapeutic targets. Eur J Cancer 42:290–294PubMedCrossRefGoogle Scholar
  24. 24.
    Blume-Jensen P, Hunter T (2001) Oncogenic kinase signalling. Nature 411:355–365PubMedCrossRefGoogle Scholar
  25. 25.
    Parsons JT, Parsons SJ (1993) Protein-tyrosine kinases, oncogenes, and cancer. Important Adv Oncol 3–17Google Scholar
  26. 26.
    Krause DS, Van Etten RA (2005) Tyrosine kinases as targets for cancer therapy. N Engl J Med 353:172–187PubMedCrossRefGoogle Scholar
  27. 27.
    Van Etten RA (2007) Oncogenic signaling: new insights and controversies from chronic myeloid leukemia. J Exp Med 204:461–465PubMedCrossRefGoogle Scholar
  28. 28.
    Sherbenou DW, Druker BJ (2007) Applying the discovery of the Philadelphia chromosome. J Clin Invest 117:2067–2074PubMedCrossRefGoogle Scholar
  29. 29.
    Jones S, Zhang X, Parsons DW, et al. (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806PubMedCrossRefGoogle Scholar
  30. 30.
    Goutsias J, Lee NH (2007) Computational and experimental approaches for modeling gene regulatory networks. Curr Pharm Des 13:1415–1436PubMedCrossRefGoogle Scholar
  31. 31.
    Hornberg JJ, Bruggeman FJ, Westerhoff HV, et al. (2006) Cancer: a systems biology disease. Biosystems 83:81–90PubMedCrossRefGoogle Scholar
  32. 32.
    Stransky B, Barrera J, Ohno-Machado L, et al. (2007) Modeling cancer: integration of “omics” information in dynamic systems. J Bioinform Comput Biol 5:977–986PubMedCrossRefGoogle Scholar
  33. 33.
    Wang E, Lenferink A, O’Connor-McCourt M (2007) Cancer systems biology: exploring cancer-associated genes on cellular networks. Cell Mol Life Sci 64:1752–1762PubMedCrossRefGoogle Scholar
  34. 34.
    Becker J (2004) Signal transduction inhibitors – a work in progress. Nat Biotechnol 22:15–18PubMedCrossRefGoogle Scholar
  35. 35.
    Griffith J, Black J, Faerman C, et al. (2004) The structural basis for autoinhibition of FLT3 by the juxtamembrane domain. Mol Cell 13:169–178PubMedCrossRefGoogle Scholar
  36. 36.
    Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225PubMedCrossRefGoogle Scholar
  37. 37.
    Van Etten RA (2003) c-Abl regulation: a tail of two lipids. Curr Biol 13:R608–R610PubMedCrossRefGoogle Scholar
  38. 38.
    Nakao M, Yokota S, Iwai T, et al. (1996) Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 10:1911–1918PubMedGoogle Scholar
  39. 39.
    Sharma SV, Bell DW, Settleman J, et al. (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181PubMedCrossRefGoogle Scholar
  40. 40.
    Smith KM, Yacobi R, Van Etten RA (2003) Autoinhibition of Bcr-Abl through its SH3 domain. Mol Cell 12:27–37PubMedCrossRefGoogle Scholar
  41. 41.
    Watanabe D, Ezoe S, Fujimoto M, et al. (2004) Suppressor of cytokine signalling-1 gene silencing in acute myeloid leukaemia and human haematopoietic cell lines. Br J Haematol 126:726–735PubMedCrossRefGoogle Scholar
  42. 42.
    Baselga J (2006) Targeting tyrosine kinases in cancer: the second wave. Science 312:1175–1178PubMedCrossRefGoogle Scholar
  43. 43.
    Traxler P (2003) Tyrosine kinases as targets in cancer therapy – successes and failures. Expert Opin Ther Targets 7:215–234PubMedCrossRefGoogle Scholar
  44. 44.
    Yarden Y (2001) The EGFR family and its ligands in human cancer: signalling mechanisms and therapeutic opportunities. Eur J Cancer 37 Suppl 4:S3–S8PubMedCrossRefGoogle Scholar
  45. 45.
    Hynes NE, Lane HA (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5:341–354PubMedCrossRefGoogle Scholar
  46. 46.
    Nicholson RI, Gee JM, Harper ME (2001) EGFR and cancer prognosis. Eur J Cancer 37 Suppl 4:S9–15PubMedCrossRefGoogle Scholar
  47. 47.
    Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al. (2003) Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798–3807PubMedCrossRefGoogle Scholar
  48. 48.
    Mendelsohn J (1992) Epidermal growth factor receptor as a target for therapy with antireceptor monoclonal antibodies. J Natl Cancer Inst Monogr 125–131Google Scholar
  49. 49.
    Rossi A, Bria E, Maione P, et al. (2008) The role of cetuximab and other epidermal growth factor receptor monoclonal antibodies in the treatment of advanced non-small cell lung cancer. Rev Recent Clin Trials 3:217–227PubMedCrossRefGoogle Scholar
  50. 50.
    Comis RL (2005) The current situation: erlotinib (Tarceva) and gefitinib (Iressa) in non-small cell lung cancer. Oncologist 10:467–470PubMedCrossRefGoogle Scholar
  51. 51.
    Siegel-Lakhai WS, Beijnen JH, Schellens JH (2005) Current knowledge and future directions of the selective epidermal growth factor receptor inhibitors erlotinib (Tarceva) and gefitinib (Iressa). Oncologist 10:579–589PubMedCrossRefGoogle Scholar
  52. 52.
    Lynch TJ, Bell DW, Sordella R, et al. (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129–2139PubMedCrossRefGoogle Scholar
  53. 53.
    Paez JG, Janne PA, Lee JC, et al. (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304:1497–1500PubMedCrossRefGoogle Scholar
  54. 54.
    Pao W, Miller V, Zakowski M, et al. (2004) 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 USA 101:13306–13311PubMedCrossRefGoogle Scholar
  55. 55.
    Rosell R, Taron M, Sanchez JJ, et al. (2007) Setting the benchmark for tailoring treatment with EGFR tyrosine kinase inhibitors. Future Oncol 3:277–283PubMedCrossRefGoogle Scholar
  56. 56.
    Sequist LV, Joshi VA, Janne PA, et al. (2007) Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist 12:90–98PubMedCrossRefGoogle Scholar
  57. 57.
    Kobayashi S, Boggon TJ, Dayaram T, et al. (2005) EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786–792PubMedCrossRefGoogle Scholar
  58. 58.
    Pao W, Miller VA, Politi KA, et al. (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73PubMedCrossRefGoogle Scholar
  59. 59.
    Balak MN, Gong Y, Riely GJ, et al. (2006) Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 12:6494–6501PubMedCrossRefGoogle Scholar
  60. 60.
    Tokumo M, Toyooka S, Ichihara S, et al. (2006) Double mutation and gene copy number of EGFR in gefitinib refractory non-small-cell lung cancer. Lung Cancer 53:117–121PubMedCrossRefGoogle Scholar
  61. 61.
    Greulich H, Chen TH, Feng W, et al. (2005) Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2:e313PubMedCrossRefGoogle Scholar
  62. 62.
    Ji H, Li D, Chen L, et al. (2006) The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell 9:485–495PubMedCrossRefGoogle Scholar
  63. 63.
    Jiang J, Greulich H, Janne PA, et al. (2005) Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression. Cancer Res 65:8968–8974PubMedCrossRefGoogle Scholar
  64. 64.
    Politi K, Zakowski MF, Fan PD, et al. (2006) Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. Genes Dev 20:1496–1510PubMedCrossRefGoogle Scholar
  65. 65.
    Sordella R, Bell DW, Haber DA, et al. (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163–1167PubMedCrossRefGoogle Scholar
  66. 66.
    Fabian MA, Biggs WH, III, Treiber DK, et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329–336PubMedCrossRefGoogle Scholar
  67. 67.
    Barber TD, Vogelstein B, Kinzler KW, et al. (2004) Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 351:2883PubMedCrossRefGoogle Scholar
  68. 68.
    Gwak GY, Yoon JH, Shin CM, et al. (2005) Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas. J Cancer Res Clin Oncol 131:649–652PubMedCrossRefGoogle Scholar
  69. 69.
    Kwak EL, Jankowski J, Thayer SP, et al. (2006) Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin Cancer Res 12:4283–4287PubMedCrossRefGoogle Scholar
  70. 70.
    Lee JW, Soung YH, Kim SY, et al. (2005) Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res 11:2879–2882PubMedCrossRefGoogle Scholar
  71. 71.
    Schilder RJ, Sill MW, Chen X, et al. (2005) Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study. Clin Cancer Res 11:5539–5548PubMedCrossRefGoogle Scholar
  72. 72.
    Bianco R, Shin I, Ritter CA, et al. (2003) Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22:2812–2822PubMedCrossRefGoogle Scholar
  73. 73.
    Engelman JA, Janne PA, Mermel C, et al. (2005) ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci USA 102:3788–3793PubMedCrossRefGoogle Scholar
  74. 74.
    Avruch J (2007) MAP kinase pathways: the first twenty years. Biochim Biophys Acta 1773:1150–1160PubMedCrossRefGoogle Scholar
  75. 75.
    Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40PubMedCrossRefGoogle Scholar
  76. 76.
    Lewis TS, Shapiro PS, Ahn NG (1998) Signal transduction through MAP kinase cascades. Adv Cancer Res 74:49–139PubMedCrossRefGoogle Scholar
  77. 77.
    Shaul YD, Seger R (2007) The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 1773:1213–1226PubMedCrossRefGoogle Scholar
  78. 78.
    English JM, Cobb MH (2002) Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci 23:40–45PubMedCrossRefGoogle Scholar
  79. 79.
    Kohno M, Pouyssegur J (2006) Targeting the ERK signaling pathway in cancer therapy. Ann Med 38:200–211PubMedCrossRefGoogle Scholar
  80. 80.
    McCubrey JA, Steelman LS, Abrams SL, et al. (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 46:249–279PubMedCrossRefGoogle Scholar
  81. 81.
    McCubrey JA, Steelman LS, Chappell WH, et al. (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773:1263–1284PubMedCrossRefGoogle Scholar
  82. 82.
    Sebolt-Leopold JS, Herrera R (2004) Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 4:937–947PubMedCrossRefGoogle Scholar
  83. 83.
    Wang D, Boerner SA, Winkler JD, et al. (2007) Clinical experience of MEK inhibitors in cancer therapy. Biochim Biophys Acta 1773:1248–1255PubMedCrossRefGoogle Scholar
  84. 84.
    Cobb MH (1999) MAP kinase pathways. Prog Biophys Mol Biol 71:479–500PubMedCrossRefGoogle Scholar
  85. 85.
    Garrington TP, Johnson GL (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11:211–218PubMedCrossRefGoogle Scholar
  86. 86.
    Widmann C, Gibson S, Jarpe MB, et al. (1999) Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79:143–180PubMedGoogle Scholar
  87. 87.
    Dhanasekaran N, Premkumar RE (1998) Signaling by dual specificity kinases. Oncogene 17:1447–1455PubMedCrossRefGoogle Scholar
  88. 88.
    Kondoh K, Nishida E (2007) Regulation of MAP kinases by MAP kinase phosphatases. Biochim Biophys Acta 1773:1227–1237PubMedCrossRefGoogle Scholar
  89. 89.
    Enslen H, Davis RJ (2001) Regulation of MAP kinases by docking domains. Biol Cell 93:5–14PubMedCrossRefGoogle Scholar
  90. 90.
    Sharrocks AD, Yang SH, Galanis A (2000) Docking domains and substrate-specificity determination for MAP kinases. Trends Biochem Sci 25:448–453PubMedCrossRefGoogle Scholar
  91. 91.
    Volmat V, Pouyssegur J (2001) Spatiotemporal regulation of the p42/p44 MAPK pathway. Biol Cell 93:71–79PubMedCrossRefGoogle Scholar
  92. 92.
    Katz M, Amit I, Yarden Y (2007) Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochim Biophys Acta 1773:1161–1176PubMedCrossRefGoogle Scholar
  93. 93.
    Rajalingam K, Schreck R, Rapp UR, et al. (2007) Ras oncogenes and their downstream targets. Biochim Biophys Acta 1773:1177–1195PubMedCrossRefGoogle Scholar
  94. 94.
    Galmiche A, Fueller J (2007) RAF kinases and mitochondria. Biochim Biophys Acta 1773:1256–1262PubMedCrossRefGoogle Scholar
  95. 95.
    Kyriakis JM (2007) The integration of signaling by multiprotein complexes containing Raf kinases. Biochim Biophys Acta 1773:1238–1247PubMedCrossRefGoogle Scholar
  96. 96.
    Leicht DT, Balan V, Kaplun A, et al. (2007) Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta 1773:1196–1212PubMedCrossRefGoogle Scholar
  97. 97.
    Crews CM, Alessandrini A, Erikson RL (1992) The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 258:478–480PubMedCrossRefGoogle Scholar
  98. 98.
    Seger R, Seger D, Lozeman FJ, et al. (1992) Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases. J Biol Chem 267:25628–25631PubMedGoogle Scholar
  99. 99.
    Boulton TG, Yancopoulos GD, Gregory JS, et al. (1990) An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249:64–67PubMedCrossRefGoogle Scholar
  100. 100.
    Chambard JC, Lefloch R, Pouyssegur J, et al. (2007) ERK implication in cell cycle regulation. Biochim Biophys Acta 1773:1299–1310PubMedCrossRefGoogle Scholar
  101. 101.
    Whitmarsh AJ (2007) Regulation of gene transcription by mitogen-activated protein kinase signaling pathways. Biochim Biophys Acta 1773:1285–1298PubMedCrossRefGoogle Scholar
  102. 102.
    Rodriguez-Viciana P, Tetsu O, Tidyman WE, et al. (2006) Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311:1287–1290PubMedCrossRefGoogle Scholar
  103. 103.
    Estep AL, Palmer C, McCormick F, et al. (2007) Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy. PLoS ONE 2:e1279PubMedCrossRefGoogle Scholar
  104. 104.
    Marks JL, Gong Y, Chitale D, et al. (2008) Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma. Cancer Res 68:5524–5528PubMedCrossRefGoogle Scholar
  105. 105.
    Cowley S, Paterson H, Kemp P, et al. (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77:841–852PubMedCrossRefGoogle Scholar
  106. 106.
    Mansour SJ, Matten WT, Hermann AS, et al. (1994) Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265:966–970PubMedCrossRefGoogle Scholar
  107. 107.
    Robinson MJ, Stippec SA, Goldsmith E, et al. (1998) A constitutively active and nuclear form of the MAP kinase ERK2 is sufficient for neurite outgrowth and cell transformation. Curr Biol 8:1141–1150PubMedCrossRefGoogle Scholar
  108. 108.
    McCubrey JA, Milella M, Tafuri A, et al. (2008) Targeting the Raf/MEK/ERK pathway with small-molecule inhibitors. Curr Opin Investig Drugs 9:614–630PubMedGoogle Scholar
  109. 109.
    Milella M, Kornblau SM, Andreeff M (2003) The mitogen-activated protein kinase signaling module as a therapeutic target in hematologic malignancies. Rev Clin Exp Hematol 7:160–190PubMedGoogle Scholar
  110. 110.
    Milella M, Precupanu CM, Gregorj C, et al. (2005) Beyond single pathway inhibition: MEK inhibitors as a platform for the development of pharmacological combinations with synergistic anti-leukemic effects. Curr Pharm Des 11:2779–2795PubMedCrossRefGoogle Scholar
  111. 111.
    Tortora G, Bianco R, Daniele G, et al. (2007) Overcoming resistance to molecularly targeted anticancer therapies: Rational drug combinations based on EGFR and MAPK inhibition for solid tumours and haematologic malignancies. Drug Resist Updat 10:81–100PubMedCrossRefGoogle Scholar
  112. 112.
    Chang F, McCubrey JA (2001) P21(Cip1) induced by Raf is associated with increased Cdk4 activity in hematopoietic cells. Oncogene 20:4354–4364PubMedCrossRefGoogle Scholar
  113. 113.
    Malumbres M, Perez dC I, Hernandez MI, et al. (2000) Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b). Mol Cell Biol 20:2915–2925PubMedCrossRefGoogle Scholar
  114. 114.
    Woods D, Parry D, Cherwinski H, et al. (1997) Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol 17:5598–5611PubMedGoogle Scholar
  115. 115.
    Kolch W (2001) To be or not to be: a question of B-Raf? Trends Neurosci 24:498–500PubMedCrossRefGoogle Scholar
  116. 116.
    Murakami MS, Morrison DK (2001) Raf-1 without MEK? Sci STKE 2001:E30CrossRefGoogle Scholar
  117. 117.
    Zha J, Harada H, Yang E, et al. (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87:619–628PubMedCrossRefGoogle Scholar
  118. 118.
    Harada H, Quearry B, Ruiz-Vela A, et al. (2004) Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc Natl Acad Sci USA 101:15313–15317PubMedCrossRefGoogle Scholar
  119. 119.
    Ley R, Balmanno K, Hadfield K, et al. (2003) Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem 278:18811–18816PubMedCrossRefGoogle Scholar
  120. 120.
    Weston CR, Balmanno K, Chalmers C, et al. (2003) Activation of ERK1/2 by deltaRaf-1:ER* represses Bim expression independently of the JNK or PI3K pathways. Oncogene 22:1281–1293PubMedCrossRefGoogle Scholar
  121. 121.
    Luciano F, Jacquel A, Colosetti P, et al. (2003) Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function. Oncogene 22:6785–6793PubMedCrossRefGoogle Scholar
  122. 122.
    Deng X, Ruvolo P, Carr B, et al. (2000) Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Proc Natl Acad Sci USA 97:1578–1583PubMedCrossRefGoogle Scholar
  123. 123.
    Deng X, Kornblau SM, Ruvolo PP, et al. (2001) Regulation of Bcl2 phosphorylation and potential significance for leukemic cell chemoresistance. J Natl Cancer Inst Monogr 30–37Google Scholar
  124. 124.
    Allan LA, Morrice N, Brady S, et al. (2003) Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nat Cell Biol 5:647–654PubMedCrossRefGoogle Scholar
  125. 125.
    Cardone MH, Roy N, Stennicke HR, et al. (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321PubMedCrossRefGoogle Scholar
  126. 126.
    O’neill E, Rushworth L, Baccarini M, et al. (2004) Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science 306:2267–2270PubMedCrossRefGoogle Scholar
  127. 127.
    Du J, Cai SH, Shi Z, et al. (2004) Binding activity of H-Ras is necessary for in vivo inhibition of ASK1 activity. Cell Res 14:148–154PubMedCrossRefGoogle Scholar
  128. 128.
    Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22PubMedCrossRefGoogle Scholar
  129. 129.
    Garnett MJ, Marais R (2004) Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6:313–319PubMedCrossRefGoogle Scholar
  130. 130.
    Davies H, Bignell GR, Cox C, et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954PubMedCrossRefGoogle Scholar
  131. 131.
    Yuen ST, Davies H, Chan TL, et al. (2002) Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62:6451–6455PubMedGoogle Scholar
  132. 132.
    Wan PT, Garnett MJ, Roe SM, et al. (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867PubMedCrossRefGoogle Scholar
  133. 133.
    Zebisch A, Staber PB, Delavar A, et al. (2006) Two transforming C-RAF germ-line mutations identified in patients with therapy-related acute myeloid leukemia. Cancer Res 66:3401–3408PubMedCrossRefGoogle Scholar
  134. 134.
    Solit DB, Garraway LA, Pratilas CA, et al. (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358–362PubMedCrossRefGoogle Scholar
  135. 135.
    Garnett MJ, Rana S, Paterson H, et al. (2005) Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol Cell 20:963–969PubMedCrossRefGoogle Scholar
  136. 136.
    Rapp UR, Gotz R, Albert S (2006) BuCy RAFs drive cells into MEK addiction. Cancer Cell 9:9–12PubMedCrossRefGoogle Scholar
  137. 137.
    Gregorj C, Ricciardi MR, Petrucci MT, et al. (2007) ERK1/2 phosphorylation is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia. Blood 109:5473–5476PubMedCrossRefGoogle Scholar
  138. 138.
    Kornblau SM, Womble M, Qiu YH, et al. (2006) Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood 108:2358–2365PubMedCrossRefGoogle Scholar
  139. 139.
    Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619PubMedCrossRefGoogle Scholar
  140. 140.
    Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657PubMedCrossRefGoogle Scholar
  141. 141.
    Katso R, Okkenhaug K, Ahmadi K, et al. (2001) Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17:615–675PubMedCrossRefGoogle Scholar
  142. 142.
    Carracedo A, Pandolfi PP (2008) The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 27:5527–5541PubMedCrossRefGoogle Scholar
  143. 143.
    Li J, Yen C, Liaw D, et al. (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947PubMedCrossRefGoogle Scholar
  144. 144.
    Steck PA, Pershouse MA, Jasser SA, et al. (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362PubMedCrossRefGoogle Scholar
  145. 145.
    Stambolic V, Suzuki A, de la Pompa JL, et al. (1998) Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell 95:29–39PubMedCrossRefGoogle Scholar
  146. 146.
    Eng C (2003) PTEN: one gene, many syndromes. Hum Mutat 22:183–198PubMedCrossRefGoogle Scholar
  147. 147.
    Walker SM, Leslie NR, Perera NM, et al. (2004) The tumour-suppressor function of PTEN requires an N-terminal lipid-binding motif. Biochem J 379:301–307PubMedCrossRefGoogle Scholar
  148. 148.
    Alessi DR, James SR, Downes CP, et al. (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261–269PubMedCrossRefGoogle Scholar
  149. 149.
    Sarbassov DD, Guertin DA, Ali SM, et al. (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101PubMedCrossRefGoogle Scholar
  150. 150.
    Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274PubMedCrossRefGoogle Scholar
  151. 151.
    Fujita N, Sato S, Katayama K, et al. (2002) Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem 277:28706–28713PubMedCrossRefGoogle Scholar
  152. 152.
    Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501PubMedCrossRefGoogle Scholar
  153. 153.
    Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22PubMedCrossRefGoogle Scholar
  154. 154.
    Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6:729–734PubMedCrossRefGoogle Scholar
  155. 155.
    Gao X, Zhang Y, Arrazola P, et al. (2002) Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 4:699–704PubMedCrossRefGoogle Scholar
  156. 156.
    Tapon N, Ito N, Dickson BJ, et al. (2001) The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105:345–355PubMedCrossRefGoogle Scholar
  157. 157.
    Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945PubMedCrossRefGoogle Scholar
  158. 158.
    Ma L, Teruya-Feldstein J, Behrendt N, et al. (2005) Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression. Genes Dev 19:1779–1786PubMedCrossRefGoogle Scholar
  159. 159.
    Manning BD, Logsdon MN, Lipovsky AI, et al. (2005) Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev 19:1773–1778PubMedCrossRefGoogle Scholar
  160. 160.
    Hresko RC, Mueckler M (2005) mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 280:40406–40416PubMedCrossRefGoogle Scholar
  161. 161.
    Jacinto E, Loewith R, Schmidt A, et al. (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122–1128PubMedCrossRefGoogle Scholar
  162. 162.
    Sarbassov DD, Ali SM, Kim DH, et al. (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302PubMedCrossRefGoogle Scholar
  163. 163.
    Kim DH, Sarbassov DD, Ali SM, et al. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175PubMedCrossRefGoogle Scholar
  164. 164.
    Kim DH, Sabatini DM (2004) Raptor and mTOR: subunits of a nutrient-sensitive complex. Curr Top Microbiol Immunol 279:259–270PubMedGoogle Scholar
  165. 165.
    Sarbassov DD, Ali SM, Sengupta S, et al. (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168PubMedCrossRefGoogle Scholar
  166. 166.
    Frias MA, Thoreen CC, Jaffe JD, et al. (2006) mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16:1865–1870PubMedCrossRefGoogle Scholar
  167. 167.
    Zeng Z, Sarbassov dD, Samudio IJ, et al. (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109:3509–3512PubMedCrossRefGoogle Scholar
  168. 168.
    Cantley LC, Auger KR, Carpenter C, et al. (1991) Oncogenes and signal transduction. Cell 64:281–302PubMedCrossRefGoogle Scholar
  169. 169.
    Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455–459PubMedCrossRefGoogle Scholar
  170. 170.
    Samuels Y, Wang Z, Bardelli A, et al. (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554PubMedCrossRefGoogle Scholar
  171. 171.
    Bachman KE, Argani P, Samuels Y, et al. (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772–775PubMedCrossRefGoogle Scholar
  172. 172.
    Campbell IG, Russell SE, Choong DY, et al. (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681PubMedCrossRefGoogle Scholar
  173. 173.
    Saal LH, Holm K, Maurer M, et al. (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559PubMedCrossRefGoogle Scholar
  174. 174.
    Broderick DK, Di C, Parrett TJ, et al. (2004) Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res 64:5048–5050PubMedCrossRefGoogle Scholar
  175. 175.
    Lee JW, Soung YH, Kim SY, et al. (2005) PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24:1477–1480PubMedCrossRefGoogle Scholar
  176. 176.
    Wu G, Mambo E, Guo Z, et al. (2005) Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J Clin Endocrinol Metab 90:4688–4693PubMedCrossRefGoogle Scholar
  177. 177.
    Parsons DW, Wang TL, Samuels Y, et al. (2005) Colorectal cancer: mutations in a signalling pathway. Nature 436:792PubMedCrossRefGoogle Scholar
  178. 178.
    Kang S, Bader AG, Vogt PK (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102:802–807PubMedCrossRefGoogle Scholar
  179. 179.
    Samuels Y, Diaz LA, Jr., Schmidt-Kittler O, et al. (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561–573PubMedCrossRefGoogle Scholar
  180. 180.
    Ikenoue T, Kanai F, Hikiba Y, et al. (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562–4567PubMedCrossRefGoogle Scholar
  181. 181.
    Wennstrom S, Downward J (1999) Role of phosphoinositide 3-kinase in activation of ras and mitogen-activated protein kinase by epidermal growth factor. Mol Cell Biol 19:4279–4288PubMedGoogle Scholar
  182. 182.
    Guan KL, Figueroa C, Brtva TR, et al. (2000) Negative regulation of the serine/threonine kinase B-Raf by Akt. J Biol Chem 275:27354–27359PubMedGoogle Scholar
  183. 183.
    Zimmermann S, Moelling K (1999) Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286:1741–1744PubMedCrossRefGoogle Scholar
  184. 184.
    Karbowniczek M, Cash T, Cheung M, et al. (2004) Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. J Biol Chem 279:29930–29937PubMedCrossRefGoogle Scholar
  185. 185.
    Yee WM, Worley PF (1997) Rheb interacts with Raf-1 kinase and may function to integrate growth factor- and protein kinase A-dependent signals. Mol Cell Biol 17:921–933PubMedGoogle Scholar
  186. 186.
    Carracedo A, Ma L, Teruya-Feldstein J, et al. (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118:3065–3074PubMedGoogle Scholar
  187. 187.
    Beck SE, Carethers JM (2007) BMP suppresses PTEN expression via RAS/ERK signaling. Cancer Biol Ther 6:1313–1317PubMedGoogle Scholar
  188. 188.
    Vasudevan KM, Burikhanov R, Goswami A, et al. (2007) Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras. Cancer Res 67:10343–10350PubMedCrossRefGoogle Scholar
  189. 189.
    Roux PP, Ballif BA, Anjum R, et al. (2004) Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 101:13489–13494PubMedCrossRefGoogle Scholar
  190. 190.
    Ma L, Chen Z, Erdjument-Bromage H, et al. (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121:179–193PubMedCrossRefGoogle Scholar
  191. 191.
    Carriere A, Cargnello M, Julien LA, et al. (2008) Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol 18:1269–1277PubMedCrossRefGoogle Scholar
  192. 192.
    Meier F, Busch S, Lasithiotakis K, et al. (2007) Combined targeting of MAPK and AKT signalling pathways is a promising strategy for melanoma treatment. Br J Dermatol 156:1204–1213PubMedCrossRefGoogle Scholar
  193. 193.
    Smalley KS, Haass NK, Brafford PA, et al. (2006) Multiple signaling pathways must be targeted to overcome drug resistance in cell lines derived from melanoma metastases. Mol Cancer Ther 5:1136–1144PubMedCrossRefGoogle Scholar
  194. 194.
    Grant S (2008) Cotargeting survival signaling pathways in cancer. J Clin Invest 118:3003–3006PubMedCrossRefGoogle Scholar
  195. 195.
    Kinkade CW, Castillo-Martin M, Puzio-Kuter A, et al. (2008) Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118:3051–3064PubMedGoogle Scholar
  196. 196.
    Weinstein IB, Joe AK (2006) Mechanisms of disease: oncogene addiction – a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 3:448–457PubMedCrossRefGoogle Scholar
  197. 197.
    Weinstein IB, Joe A (2008) Oncogene addiction. Cancer Res 68:3077–3080PubMedCrossRefGoogle Scholar
  198. 198.
    Felsher DW, Bishop JM (1999) Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 4:199–207PubMedCrossRefGoogle Scholar
  199. 199.
    D’Cruz CM, Gunther EJ, Boxer RB, et al. (2001) c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nat Med 7:235–239PubMedCrossRefGoogle Scholar
  200. 200.
    Moody SE, Sarkisian CJ, Hahn KT, et al. (2002) Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell 2:451–461PubMedCrossRefGoogle Scholar
  201. 201.
    Moody SE, Perez D, Pan TC, et al. (2005) The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8:197–209PubMedCrossRefGoogle Scholar
  202. 202.
    Gunther EJ, Moody SE, Belka GK, et al. (2003) Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis. Genes Dev 17:488–501PubMedCrossRefGoogle Scholar
  203. 203.
    Kornmann M, Danenberg KD, Arber N, et al. (1999) Inhibition of cyclin D1 expression in human pancreatic cancer cells is associated with increased chemosensitivity and decreased expression of multiple chemoresistance genes. Cancer Res 59:3505–3511PubMedGoogle Scholar
  204. 204.
    Bria E, Cuppone F, Milella M, et al. (2008) Trastuzumab cardiotoxicity: biological hypotheses and clinical open issues. Expert Opin Biol Ther 8:1963–1971PubMedCrossRefGoogle Scholar
  205. 205.
    Bria E, Cuppone F, Fornier M, et al. (2008) Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: the dark side of the moon? A meta-analysis of the randomized trials. Breast Cancer Res Treat 109:231–239PubMedCrossRefGoogle Scholar
  206. 206.
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659–1672PubMedCrossRefGoogle Scholar
  207. 207.
    Slamon DJ, Leyland-Jones B, Shak S, et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  208. 208.
    McCubrey JA, Steelman LS, Abrams SL, et al. (2008) Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 22:708–722PubMedCrossRefGoogle Scholar
  209. 209.
    Misaghian N, Ligresti G, Steelman LS, et al. (2008) Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. LeukemiaGoogle Scholar
  210. 210.
    Steelman LS, Abrams SL, Whelan J, et al. (2008) Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia 22:686–707PubMedCrossRefGoogle Scholar
  211. 211.
    Demetri GD, von Mehren M, Blanke CD, et al. (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472–480PubMedCrossRefGoogle Scholar
  212. 212.
    Hughes TP, Kaeda J, Branford S, et al. (2003) Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423–1432PubMedCrossRefGoogle Scholar
  213. 213.
    Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174PubMedCrossRefGoogle Scholar
  214. 214.
    Gorre ME, Mohammed M, Ellwood K, et al. (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880PubMedCrossRefGoogle Scholar
  215. 215.
    La RP, Corbin AS, Stoffregen EP, et al. (2002) Activity of the Bcr-Abl kinase inhibitor PD180970 against clinically relevant Bcr-Abl isoforms that cause resistance to imatinib mesylate (Gleevec, STI571). Cancer Res 62:7149–7153Google Scholar
  216. 216.
    Kwak EL, Sordella R, Bell DW, et al. (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665–7670PubMedCrossRefGoogle Scholar
  217. 217.
    Weinstein IB (2000) Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Carcinogenesis 21:857–864PubMedCrossRefGoogle Scholar
  218. 218.
    Weinstein IB (2002) Cancer. Addiction to oncogenes – the Achilles heal of cancer. Science 297:63–64PubMedCrossRefGoogle Scholar
  219. 219.
    Kaelin WG, Jr. (2005) The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 5:689–698PubMedCrossRefGoogle Scholar
  220. 220.
    Mills GB, Lu Y, Kohn EC (2001) Linking molecular therapeutics to molecular diagnostics: inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc Natl Acad Sci USA 98:10031–10033PubMedCrossRefGoogle Scholar
  221. 221.
    Mellinghoff IK, Wang MY, Vivanco I, et al. (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024PubMedCrossRefGoogle Scholar
  222. 222.
    Sharma SV, Gajowniczek P, Way IP, et al. (2006) A common signaling cascade may underlie “addiction” to the Src, BCR-ABL, and EGF receptor oncogenes. Cancer Cell 10:425–435PubMedCrossRefGoogle Scholar
  223. 223.
    Mukohara T, Engelman JA, Hanna NH, et al. (2005) Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 97:1185–1194PubMedCrossRefGoogle Scholar
  224. 224.
    Evan G, Littlewood T (1998) A matter of life and cell death. Science 281:1317–1322PubMedCrossRefGoogle Scholar
  225. 225.
    Felsher DW (2008) Oncogene addiction versus oncogene amnesia: perhaps more than just a bad habit? Cancer Res 68:3081–3086PubMedCrossRefGoogle Scholar
  226. 226.
    Lowe SW, Cepero E, Evan G (2004) Intrinsic tumour suppression. Nature 432:307–315PubMedCrossRefGoogle Scholar
  227. 227.
    Wu CH, van Riggelen J, Yetil A, et al. (2007) Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc Natl Acad Sci USA 104:13028–13033PubMedCrossRefGoogle Scholar
  228. 228.
    Shepherd FA, Rodrigues PJ, Ciuleanu T, et al. (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132PubMedCrossRefGoogle Scholar
  229. 229.
    Moore MJ, Goldstein D, Hamm J, et al. (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966PubMedCrossRefGoogle Scholar
  230. 230.
    Thatcher N, Chang A, Parikh P, et al. (2005) Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 366:1527–1537PubMedCrossRefGoogle Scholar
  231. 231.
    Kelly K, Chansky K, Gaspar LE, et al. (2008) Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 26:2450–2456PubMedCrossRefGoogle Scholar
  232. 232.
    Simon R, Maitournam A (2004) Evaluating the efficiency of targeted designs for randomized clinical trials. Clin Cancer Res 10:6759–6763PubMedCrossRefGoogle Scholar
  233. 233.
    Miller K, Wang M, Gralow J, et al. (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676PubMedCrossRefGoogle Scholar
  234. 234.
    Schneider BP, Wang M, Radovich M, et al. (2008) Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol 26:4672–4678PubMedCrossRefGoogle Scholar
  235. 235.
    Vickers AJ, Ballen V, Scher HI (2007) Setting the bar in phase II trials: the use of historical data for determining “go/no go” decision for definitive phase III testing. Clin Cancer Res 13:972–976PubMedCrossRefGoogle Scholar
  236. 236.
    Ratain MJ, Karrison TG (2007) Testing the wrong hypothesis in phase II oncology trials: there is a better alternative. Clin Cancer Res 13:781–782PubMedCrossRefGoogle Scholar
  237. 237.
    Chan JK, Ueda SM, Sugiyama VE, et al. (2008) Analysis of phase II studies on targeted agents and subsequent phase III trials: what are the predictors for success? J Clin Oncol 26:1511–1518PubMedCrossRefGoogle Scholar
  238. 238.
    Karaman MW, Herrgard S, Treiber DK, et al. (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127–132PubMedCrossRefGoogle Scholar
  239. 239.
    Di LA, Moretti E (2008) Anthracyclines: the first generation of cytotoxic targeted agents? A possible dream. J Clin Oncol 26:5011–5013CrossRefGoogle Scholar
  240. 240.
    Llovet JM, Ricci S, Mazzaferro V, et al. (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390PubMedCrossRefGoogle Scholar
  241. 241.
    Motzer RJ, Hutson TE, Tomczak P, et al. (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124PubMedCrossRefGoogle Scholar
  242. 242.
    El-Maraghi RH, Eisenhauer EA (2008) Review of phase II trial designs used in studies of molecular targeted agents: outcomes and predictors of success in phase III. J Clin Oncol 26:1346–1354PubMedCrossRefGoogle Scholar
  243. 243.
    Lagakos SW (2006) The challenge of subgroup analyses – reporting without distorting. N Engl J Med 354:1667–1669PubMedCrossRefGoogle Scholar
  244. 244.
    Karapetis CS, Khambata-Ford S, Jonker DJ, et al. (2008) K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 359:1757–1765PubMedCrossRefGoogle Scholar
  245. 245.
    Amado RG, Wolf M, Peeters M, et al. (2008) Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626–1634PubMedCrossRefGoogle Scholar
  246. 246.
    Freidlin B, Simon R (2005) Adaptive signature design: an adaptive clinical trial design for generating and prospectively testing a gene expression signature for sensitive patients. Clin Cancer Res 11:7872–7878PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Michele Milella
    • 1
    Email author
  • Ludovica Ciuffreda
    • 1
  • Emilio Bria
    • 1
  1. 1.Division of Medical Oncology A (MM and LC) and C (EB)Regina Elena National Cancer InstituteRomeItaly

Personalised recommendations