Role of the NF-κB transcriptome and proteome as biomarkers human head and neck squamous cell carcinomas

Biomarkers in Medicine

Volumn 2, Issue 4, 2008, Pages 409-429

  Chen, Zhong ^a   Yan, Bin ^a   Van Waes, Carter ^a  

^a NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS   (United States)

Author keywords

Head and neck cancer; NF B; Proteome; Signal pathways; Transcriptome

Indexed keywords

3 PHENYLSULFAMOYLCINNAMOHYDROXAMIC ACID; BETA CATENIN; BIOLOGICAL MARKER; BORTEZOMIB; EPHRIN RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; GEFITINIB; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; HEAT SHOCK PROTEIN 90 INHIBITOR; HISTONE DEACETYLASE INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INOSITOL PHOSPHATE; INTEGRIN; INTERLEUKIN 6; KI 67 ANTIGEN; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38; NEU DIFFERENTIATION FACTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PROTEINASE INHIBITOR; PROTEOME; SOMATOMEDIN C; STRESS ACTIVATED PROTEIN KINASE; TRANSCRIPTOME; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN; WNT PROTEIN;

ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; BINDING SITE; CANCER CELL CULTURE; CANCER RISK; CANCER SURVIVAL; CELL PROLIFERATION; CELL SURVIVAL; CLINICAL TRIAL; DRUG POTENTIATION; DRUG RESPONSE; DRUG TARGETING; GENE ACTIVATION; HEAD AND NECK CARCINOMA; HUMAN; IMMUNOHISTOCHEMISTRY; NICK END LABELING; NONHUMAN; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN BLOOD LEVEL; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN TARGETING; REVIEW; RISK ASSESSMENT; SIGNAL TRANSDUCTION; SQUAMOUS CELL CARCINOMA;

EID: 54849417812     PISSN: 17520363     EISSN: None     Source Type: Journal    
DOI: 10.2217/17520363.2.4.409     Document Type: Review

References (110)

1. Hayden MS, Ghosh S: Shared principles in NF-κB signaling. Cell 132, 344-362 (2008).
2. Van Waes C: Nuclear factor-κB in development, prevention, and therapy of cancer. Clin. Cancer Res. 13, 1076-1082 (2007).
3. Karin M: Nuclear factor-κB in cancer development and progression. Nature 441, 431-436 (2006).
4. Basseres DS, Baldwin AS: Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression. Oncogene 25, 6817-6830 (2006).
5. Allen CT, Ricker JL, Chen Z, Van Waes C: Role of activated nuclear factor-κB in the pathogenesis and therapy of squamous cell carcinoma of the head and neck. Head Neck 29, 959-971 (2007).
6. Ondrey FG, Dong G, Sunwoo J et al.: Constitutive activation of transcription factors NF-(κ)B, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflammatory and pro-angiogenic cytokines. Mol. Carcinog. 26, 119-129 (1999).
7. Duffey DC, Chen Z, Dong G et al.: Expression of a dominant-negative mutant inhibitor-κBα of nuclear factor-κB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo. Cancer Res. 59, 3468-3474 (1999).
8. Zhang PL, Pellitteri PK, Law A et al.: Overexpression of phosphorylated nuclear factor-κB in tonsillar squamous cell carcinoma and high-grade dysplasia is associated with poor prognosis. Mod. Pathol. 18, 924-932 (2005).
9. Yu M, Yeh J, Van Waes C: Protein kinase casein kinase 2 mediates inhibitor-κB kinase and aberrant nuclear factor-κB activation by serum factor(s) in head and neck squamous carcinoma cells. Cancer Res. 66, 6722-6731 (2006).
10. Allen C, Saigal K, Nottingham L, Chen Z, Van Waes C: Bortezomib-induced apoptosis with limited clinical response is accompanied by inhibition of canonical but not alternative NF-κB subunits or other prosurvival signal pathways activated in head and neck cancer. Clin. Cancer Res. (2008) (In Press).
11. Bancroft CC, Chen Z, Dong G et al.: Coexpression of proangiogenic factors IL-8 and VEGF by human head and neck squamous cell carcinoma involves coactivation by MEK-MAPK and IKK-NF-κB signal pathways. Clin. Cancer Res. 7, 435-442 (2001).
12. Chen Z, Malhotra PS, Thomas GR et al.: Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer. Clin. Cancer Res. 5, 1369-1379 (1999).
13. Loukinova E, Dong G, Enamorado-Ayalya I et al.: Growth regulated oncogene-α expression by murine squamous cell carcinoma promotes tumor growth, metastasis, leukocyte infiltration and angiogenesis by a host CXC receptor-2 dependent mechanism. Oncogene 19, 3477-3486 (2000).
14. Chen Z, Colon I, Ortiz N et al.: Effects of interleukin-1α, interleukin-1 receptor antagonist, and neutralizing antibody on proinflammatory cytokine expression by human squamous cell carcinoma lines. Cancer Res. 58, 3668-3676 (1998).
15. Druzgal CH, Chen Z, Yeh NT et al.: A pilot study of longitudinal serum cytokine and angiogenesis factor levels as markers of therapeutic response and survival in patients with head and neck squamous cell carcinoma. Head Neck 27, 771-784 (2005).
16. Smith CW, Chen Z, Dong G et al.: The host environment promotes the development of primary and metastatic squamous cell carcinomas that constitutively express proinflammatory cytokines IL-1α, IL-6, GM-CSF, and KC. Clin. Exp. Metastasis 16, 655-664 (1998).
17. Tamura M, Arakaki N, Tsubouchi H, Takada H, Daikuhara Y: Enhancement of human hepatocyte growth factor production by interleukin-1α and -1β and tumor necrosis factor-α by fibroblasts in culture. J. Biol. Chem. 268, 8140-8145 (1993).
18. Dong G, Chen Z, Li ZY, Yeh NT, Bancroft CC, Van Waes C: Hepatocyte growth factor/scatter factor-induced activation of MEK and PI3K signal pathways contributes to expression of proangiogenic cytokines interleukin-8 and vascular endothelial growth factor in head and neck squamous cell carcinoma. Cancer Res. 61, 5911-5918 (2001).
19. Allen C, Duffy S, Teknos T et al.: Nuclear factor-κB-related serum factors as longitudinal biomarkers of response and survival in advanced oropharyngeal carcinoma. Clin. Cancer Res. 13, 3182-3190 (2007).
20. Loukinova E, Chen Z, Van Waes C, Dong G: Expression of proangiogenic chemokine GRO-1 in low and high metastatic variants of Pam murine squamous cell carcinoma is differentially regulated by IL-1α, EGF and TGF-β1 through NF-κB dependent and independent mechanisms. Int. J. Cancer 94, 637-644 (2001).
21. Wolf JS, Chen Z, Dong G et al.: IL (interleukin)-1α promotes nuclear factor-κB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas. Clin. Cancer Res. 7, 1812-1820 (2001).
22. Hong SH, Ondrey FG, Avis IM et al.: Cyclooxygenase regulates human oropharyngeal carcinomas via the proinflammatory cytokine IL-6: a general role for inflammation? FASEB J. 14, 1499-1507 (2000).
23. Lee TL, Yang XP, Yan B et al.: A novel nuclear factor-κB gene signature is differentially expressed in head and neck squamous cell carcinomas in association with TP53 status. Clin. Cancer Res. 13, 5680-5691 (2007).
24. Yan B, Yang X, Lee TL et al.: Genome-wide identification of novel expression signatures reveal distinct patterns and prevalence of binding motifs for p53, nuclear factor-κB and other signal transcription factors in head and neck squamous cell carcinoma. Genome Biol. 8, R78 (2007).
25. Yan B, Chen G, Saigal K et al.: Systems biology-defined NF-κB regulons, interacting signal pathways and networks are implicated in the malignant phenotype of head and neck cancer cell lines differing in p53 status. Genome Biol. 9, R53 (2008).
26. Singh S, Sadanandam A, Singh RK: Chemokines in tumor angiogenesis and metastasis. Cancer Metastasis Rev. 26, 453-467 (2007).
27. Dong G, Loukinova E, Chen Z et al.: Molecular profiling of transformed and metastatic murine squamous carcinoma cells by differential display and cDNA microarray reveals altered expression of multiple genes related to growth, apoptosis, angiogenesis, and the NF-κB signal pathway. Cancer Res. 61, 4797-4808 (2001).
28. Loercher A, Lee TL, Ricker JL et al.: Nuclear factor-κB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res. 64, 6511-6523 (2004).
29. Kitadai Y, Takahashi Y, Haruma K et al.: Transfection of interleukin-8 increases angiogenesis and tumorigenesis of human gastric carcinoma cells in nude mice. Br. J. Cancer 81, 647-653 (1999).
30. Lee TL, Yeh J, C Van Waes, Chen Z: Epigenetic modification of SOCS-1 differentially regulates STAT3 activation in response to interleukin-6 receptor and epidermal growth factor receptor signaling through JAK and/ or MEK in head and neck squamous cell carcinomas. Mol. Cancer Ther. 5, 8-19 (2006).
31. Van Waes C, Chang AA, PF Lebowitz et al.: Inhibition of nuclear factor-2kB and target genes during combined therapy with proteasome inhibitor bortezomib and reirradiation in patients with recurrent head-and-neck squamous cell carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 63, 1400-1412 (2005).
32. Ruan HY, Masuda M, A Ito et al.: Effects of a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on growth, apoptosis, gene expression, and chemosensitivity in head and neck squamous cell carcinoma cell lines. Head Neck 28, 158-165 (2006).
33. Bancroft CC, Chen Z, J Yeh et al.: Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF-κB and AP-1 activation and IL-8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int. J. Cancer 99, 538-548 (2002).
34. Riedel F, Gotte K, Schwalb J, Wirtz H, Bergler W, Hormann K: Serum levels of vascular endothelial growth factor in patients with head and neck cancer. Eur. Arch. Otorhinolaryngol. 257, 332-336 (2000).
35. Choi P, Chen C: Genetic expression profiles and biologic pathway alterations in head and neck squamous cell carcinoma. Cancer 104, 1113-1128 (2005).
36. Roepman P, Kemmeren P, Wessels LF, Slootweg PJ, Holstege FC: Multiple robust signatures for detecting lymph node metastasis in head and neck cancer. Cancer Res. 66, 2361-2366 (2006).
37. Hunter KD, Thurlow JK, Fleming F et al.: Divergent routes to oral cancer. Cancer Res. 66, 7405-7413 (2006).
38. Chung CH, Parker JS, Ely K et al.: Gene Expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-κB signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res. 66, 8210-8218 (2006).
39. Roepman P, de Jager A, Groot Koerkamp MJ, Kummer JA, Slootweg PJ, Holstege FC: Maintenance of head and neck tumor gene expression profiles upon lymph node metastasis. Cancer Res. 66, 11110-11114 (2006).
40. Friedman J, Nottingham L, Duggal P et al.: Deficient TP53 expression, function, and cisplatin sensitivity are restored by quinacrine in head and neck cancer. Clin. Cancer Res. 13, 6568-6578 (2007).
41. Worden B, Yang XP, TL Lee et al.: Hepatocyte growth factor/scatter factor differentially regulates expression of proangiogenic factors through Egr-1 in head and neck squamous cell carcinoma. Cancer Res. 65, 7071-7080 (2005).
42. Piccolo E, Vignati S, T Maffucci et al.: Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway. Oncogene 23, 1754-1765 (2004).
43. Cataisson C, Joseloff E, R Murillas et al.: Activation of cutaneous protein kinase C-α induces keratinocyte apoptosis and intraepidermal inflammation by independent signaling pathways. J. Immunol. 171, 2703-2713 (2003).
44. Hou P, Liu D, Shan Y et al.: Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. Clin. Cancer Res. 13, 1161-1170 (2007).
45. Blanpain C, Horsley V, Fuchs E: Epithelial stem cells: turning over new leaves. Cell 128, 445-458 (2007).
46. Lu SL, Herrington H, Reh D et al.: Loss of transforming growth factor-β type II receptor promotes metastatic head-and-neck squamous cell carcinoma. Genes Dev. 20, 1331-1342 (2006).
47. Bradford CR, Zhu S, Ogawa H et al.: P53 mutation correlates with cisplatin sensitivity in head and neck squamous cell carcinoma lines. Head Neck 25, 654-661 (2003).
48. Ongkeko WM, Altuna X, Weisman RA, Wang-Rodriguez J: Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am. J. Clin. Pathol. 124, 71-76 (2005).
49. Chen Z, Ricker J, Chang A et al.: Identification of differences in sensitivity and proteasome-dependent molecular correlates in head and neck squamous cell carcinoma cells following treatment with proteasome inhibitor bortezomib (VELCADETM, formerly PS-341). Mol. Cancer Ther. (2008) (In Press).
50. Duan J, Friedman J, Nottingham L, Chen Z, Ara G, Van Waes C: Nuclear factor-κB p65 small interfering RNA or proteasome inhibitor bortezomib sensitizes head and neck squamous cell carcinomas to classic histone deacetylase inhibitors and novel histone deacetylase inhibitor PXD101. Mol. Cancer Ther. 6, 37-50 (2007).
51. Lee TL, Yeh J, Friedman J et al.: A signal network involving coactivated NF-κB and STAT3 and altered p53 modulates BAX/BCL-XL expression and promotes cell survival of head and neck squamous cell carcinomas. Int. J. Cancer 122, 1987-1998 (2008).
52. Chen Z, Smith CW, Kiel D, Van Waes C: Metastatic variants derived following in vivo tumor progression of an in vitro transformed squamous cell carcinoma line acquire a differential growth advantage requiring tumor-host interaction. Clin. Exp. Metastasis 15, 527-537 (1997).
53. Dong G, Chen Z, Kato T, Van Waes C: The host environment promotes the constitutive activation of nuclear factor-κB and proinflammatory cytokine expression during metastatic tumor progression of murine squamous cell carcinoma. Cancer Res. 59, 3495-3504 (1999).
54. Lo Muzio L, Staibano S, Pannone G et al.: β- and γ-catenin expression in oral squamous cell carcinomas. Anticancer Res. 19, 3817-3826 (1999).
55. Adams J: The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5, 417-421 (2004).
56. Adams J, Palombella VJ, Sausville EA et al.: Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 59, 2615-2622 (1999).
57. An J, Sun Y, Fisher M, Rettig MB: Maximal apoptosis of renal cell carcinoma by the proteasome inhibitor bortezomib is nuclear factor-κB dependent. Mol. Cancer Ther. 3, 727-736 (2004).
58. Dai Y, Rahmani M, Grant S: Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-κB-dependent process. Oncogene 22, 7108-7122 (2003).
59. Hipp MS, Urbich C, Mayer P et al.: Proteasome inhibition leads to NF-κB-independent IL-8 transactivation in human endothelial cells through induction of AP-1. Eur. J. Immunol. 32, 2208-2217 (2002).
60. Podar K, Raab MS, Tonon G et al.: Up-regulation of c-Jun inhibits proliferation and induces apoptosis via caspase-triggered c-Abl cleavage in human multiple myeloma. Cancer Res. 67, 1680-1688 (2007).
61. Tai YT, Fulciniti M, Hideshima T et al.: Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood 110, 1656-1663 (2007).
62. Kojima K, Konopleva M, Samudio IJ, Ruvolo V, Andreeff M: Mitogen-activated protein kinase kinase inhibition enhances nuclear proapoptotic function of p53 in acute myelogenous leukemia cells. Cancer Res. 67, 3210-3219 (2007).
63. Navas TA, Nguyen AN, Hideshima T et al.: Inhibition of p38a MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. Leukemia 20, 1017-1027 (2006).
64. Johnson TR, Stone K, Nikrad M et al.: The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. Oncogene 22, 4953-4963 (2003).
65. Yang Y, Ikezoe T, Saito T, Kobayashi M, Koeffler HP, Taguchi H: Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling. Cancer Sci. 95, 176-180 (2004).
66. Yu J, Tiwari S, Steiner P, Zhang L: Differential apoptotic response to the proteasome inhibitor Bortezomib [VELCADE, PS-341] in Bax-deficient and p21-deficient colon cancer cells. Cancer Biol. Ther. 2, 694-649 (2003).
67. Fribley A, Zeng Q, Wang CY: Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells. Mol. Cell Biol. 24, 9695-9704 (2004).
68. Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ: Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts. Mol. Cancer Ther. 2, 835-843 (2003).
69. Sunwoo JB, Chen Z, Dong G et al.: Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-κ B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin. Cancer Res. 7, 1419-1428 (2001).
70. Nawrocki ST, Bruns CJ, Harbison MT et al.: Effects of the proteasome inhibitor PS-341 on apoptosis and angiogenesis in orthotopic human pancreatic tumor xenografts. Mol. Cancer Ther. 1, 1243-1253 (2002).
71. Van Waes C, Sunwoo JB, De Graff W et al.: Radio sensitization and proteasome inhibition. In: Cancer Drug Discovery and Development: Proteasome Inhibitors in Cancer Therapy. Adams J, Totowa NJ (Eds). Humana, Louisville, KY, USA 123-131 (2004).
72. Nawrocki ST, Carew JS, Pino MS MS et al.: Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res. 66, 3773-3781 (2006).
73. Jung M: Inhibitors of histone deacetylase as new anticancer agents. Curr. Med. Chem. 8, 1505-1511 (2001).
74. Marks PA, Richon VM, Miller T, Kelly WK: Histone deacetylase inhibitors. Adv. Cancer Res. 91, 137-168 (2004).
75. Marks PA, Dokmanovic M: Histone deacetylase inhibitors: discovery and development as anticancer agents. Expert Opin. Investig. Drugs 14, 1497-1511 (2005).
76. Marks PA, Richon VM, Rifkind RA: Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J. Natl Cancer Inst. 92, 1210-1216 (2000).
77. Gillenwater A, Xu XC, Estrov Y, Sacks PG, Lotan D, Lotan R: Modulation of galectin-1 content in human head and neck squamous carcinoma cells by sodium butyrate. Int. J. Cancer 75, 217-224 (1998).
78. Saunders N, Dicker A, Popa C, Jones S, Dahler A: Histone deacetylase inhibitors as potential anti-skin cancer agents. Cancer Res. 59, 399-404 (1999).
79. Coombes MM, Briggs KL, Bone JR, Clayman GL, El-Naggar AK, Dent SY: Resetting the histone code at CDKN2A in HNSCC by inhibition of DNA methylation. Oncogene 22, 8902-8911 (2003).
80. Zhang Y, Jung M, Dritschilo A, Jung M: Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors. Radiat. Res. 161, 667-674 (2004).
81. Chen L, Fischle W, Verdin E, Greene WC: Duration of nuclear NF-κB action regulated by reversible acetylation. Science 293, 1653-1657 (2001).
82. Chen LF, Mu Y, Greene WC: Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-κB. EMBO J. 21, 6539-6548 (2002).
83. Thelemann A, Petti F, Griffin G et al.: Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells. Mol. Cell. Proteomics 4, 356-376 (2005).
84. Santini J, Formento JL, Francoual M et al.: Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas. Head Neck 13, 132-139 (1991).
85. Dassonville O, Formento JL, Francoual M et al.: Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer. J. Clin. Oncol. 11, 1873-1878 (1993).
86. Rogers SJ, Harrington KJ, Rhys-Evans P, O-Charoenrat P, Eccles SA: Biological significance of c-erbB family oncogenes in head and neck cancer. Cancer Metastasis Rev. 24, 47-69 (2005).
87. Kalyankrishna S, Grandis JR: Epidermal growth factor receptor biology in head and neck cancer. J. Clin. Oncol. 24, 2666-2672 (2006).
88. Azim HA Jr, Ganti AK: Targeted therapy in advanced non-small cell lung cancer (NSCLC): where do we stand? Cancer Treat. Rev. 32, 630-636 (2006).
89. Kris MG, Natale RB, Herbst RS et al.: A Phase II trial of ZD1839 ('Iressa') in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum and docetaxel-based regimens (IDEAL 2). Proc. Am. Soc. Clin. Oncol. 21, 1166 (2002).
90. Fukuoka M, Yano S, Giaccone G et al.: Final results from a Phase II trial of ZD1839 ('Iressa') for patients with advanced non-small-cell lung cancer (IDEAL 1). Proc. Am. Soc. Clin. Oncol. 21, 1188 (2002).
91. Ranson M, Hammond LA, Ferry D et al.: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a Phase I trial. J. Clin. Oncol. 20, 2240-2250 (2002).
92. Baselga J, Rischin D, Ranson M et al.: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J. Clin. Oncol. 20, 4292-4302 (2002).
93. Cappuzzo F, Magrini E, Ceresoli GL et al.: Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J. Natl Cancer Inst. 96, 1133-1141 (2004).
94. Hirsch FR, Varella-Garcia M, Bunn PA Jr et al.: Molecular predictors of outcome with gefitinib in a Phase III placebo-controlled study in advanced non-small-cell lung cancer. J. Clin. Oncol. 24, 5034-5042 (2006).
95. Sok JC, Coppelli FM, Thomas SM et al.: Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin. Cancer Res. 12, 5064-5073 (2006).
96. Pomerantz RG, Grandis JR: The epidermal growth factor receptor signaling network in head and neck carcinogenesis and implications for targeted therapy. Semin. Oncol. 31, 734-743 (2004).
97. Boerner JL, Biscardi JS, Silva CM, Parsons SJ: Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis. Mol. Carcinog. 44, 262-273 (2005).
98. Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C: PI3K/Akt and apoptosis: size matters. Oncogene 22, 8983-8998 (2003).
99. She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N: The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 8, 287-297 (2005).
100. Zebisch A, Czernilofsky AP, Keri G, Smigelskaite J, Sill H, Troppmair J: Signaling through RAS-RAF-MEK-ERK: from basics to bedside. Curr. Med. Chem. 14, 601-623 (2007).
101. Okabe T, Okamoto I, Tamura K et al.: Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification. Cancer Res. 67, 2046-2053 (2007).
102. 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. 350, 2129-2139 (2004).
103. 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. USA 101, 13306-13311 (2004).
104. Paez JG, Janne PA, Lee JC et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497-1500 (2004).
105. Mitsudomi T, Kosaka T, Endoh H et al.: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J. Clin. Oncol. 23, 2513-2520 (2005).
106. Mitsudomi T, Kosaka T, Yatabe Y: Biological and clinical implications of EGFR mutations in lung cancer. Int. J. Clin. Oncol. 11, 190-198 (2006).
107. Noro R, Gemma A, Kosaihira S et al.: Gefitinib (IRESSA) sensitive lung cancer cell lines show phosphorylation of Akt without ligand stimulation. BMC Cancer 6, 277 (2006).
108. Calvo KR, Liotta LA, Petricoin EF: Clinical proteomics: from biomarker discovery and cell signaling profiles to individualized personal therapy. Biosci. Rep. 25, 107-125 (2005).
109. Hingorani SR, Petricoin EF, Maitra A et al.: Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437-450 (2003).
110. Nishizuka S, Charboneau L, Young L et al.: Proteomic profiling of the NCI-60 cancer cell lines using new high-density reverse-phase lysate microarrays. Proc. Natl Acad. Sci. USA 100, 14229-14234 (2003).