HER family inhibitors in pancreatic cancer: Current status and future directions

Expert Opinion on Therapeutic Targets

Volumn 11, Issue 3, 2007, Pages 337-347

  Berz, David ^a   Miner, Thomas ^a   McCormack, Elise ^a   Safran, Howard ^a  

^a Brown University Oncology Group   (United States)

Author keywords

EGFR; HER inhibitor; Pancreatic cancer

Indexed keywords

CAPECITABINE; CARBOPLATIN; CETUXIMAB; CISPLATIN; EPIDERMAL GROWTH FACTOR; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR; ERLOTINIB; FLUOROURACIL; GEFITINIB; GEMCITABINE; GROWTH FACTOR RECEPTOR; LAPATINIB; MATUZUMAB; MESSENGER RNA; MITOGEN ACTIVATED PROTEIN KINASE; OXALIPLATIN; PACLITAXEL; PANITUMUMAB; PELITINIB; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PLACEBO; PROTEIN KINASE B; RADIOSENSITIZING AGENT; STAT PROTEIN; TRANSFORMING GROWTH FACTOR ALPHA; TRASTUZUMAB; UNINDEXED DRUG;

ABDOMINAL PAIN; ADVANCED CANCER; ANTINEOPLASTIC ACTIVITY; ASTHENIA; BILE DUCT CANCER; BODY WEIGHT DISORDER; BONE MARROW SUPPRESSION; CANCER RADIOTHERAPY; CANCER STAGING; CANCER SURVIVAL; CHIMERA; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CYTOTOXICITY; DIARRHEA; DRUG DOSE ESCALATION; DRUG ERUPTION; DRUG FATALITY; DRUG POTENTIATION; DRUG TARGETING; DRUG WITHDRAWAL; ENTEROPATHY; FATIGUE; FEVER; GASTROINTESTINAL SYMPTOM; GENE OVEREXPRESSION; GENE TARGETING; GUILLAIN BARRE SYNDROME; HEADACHE; HEART LEFT VENTRICLE EJECTION FRACTION; HEMATOLOGIC DISEASE; HUMAN; IMMUNOHISTOCHEMISTRY; INTERSTITIAL PNEUMONIA; LEUKOPENIA; LUNG NON SMALL CELL CANCER; MULTIPLE CYCLE TREATMENT; NAUSEA; NEUROTOXICITY; NEUTROPENIA; PANCREAS CANCER; PROTEIN DOMAIN; RANDOMIZED CONTROLLED TRIAL; REVIEW; SIDE EFFECT; STOMATITIS; THROMBOCYTOPENIA; UNSPECIFIED SIDE EFFECT; VOMITING;

ANTINEOPLASTIC AGENTS; CLINICAL TRIALS; HUMANS; PANCREATIC NEOPLASMS; PROTEIN KINASE INHIBITORS; RECEPTOR, EPIDERMAL GROWTH FACTOR; RECEPTOR, ERBB-2;

EID: 33847119422     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.11.3.337     Document Type: Review

References (109)

1. JEMAL A, SIEGEL R, WARD E et al.: Cancer statistics, 2006. CA Cancer J. Clin. (2006) 56(2):106-130.
2. ROTHENBERG ML, MOORE MJ, CRIPPS MC et al.: A Phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann. Oncol. (1996) 7(4):347-353.
3. CARMICHAEL J, FINK U, RUSSELL RC et al.: Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br. J. Cancer (1996) 73(1):101-105.
4. BURRIS HA III, MOORE MJ, ANDERSEN J et al.: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. (1997) 15(6):2403-2413.
5. CASCINU S, GASPARINI G, CATALANO V et al.: A Phase I-II study of gemcitabine and docetaxel in advanced pancreatic cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Ann. Oncol. (1999) 10(11):1377-1379.
6. MOORSEL CJ, PINEDO HM, VEERMAN G et al.: Mechanisms of synergism between cisplatin and gemcitabine in ovarian and non-small cell lung cancer cell lines. Br. J. Cancer (1999) 80(7):981-990.
7. LOUVET C, LABIANCA R, HAMMEL P et al.: Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD Phase III trial. J. Clin. Oncol. (2005) 23(15):3509-3516.
8. ROCHA LIMA CM, ROTCHE R, JEFFERY M et al.: A randomized Phase III study comparing efficacy and safety of gemcitabine and irinotecan to gemcitabine alone in patients with locally advanced or metastatic pancreatic cancer who have not received prior systemic therapy (abstract). Proc. Am. Soc. Clin. Oncol. (2003) 22:251a.
9. CONROY T, PAILLOT B, FRANCOIS E et al.: Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer-a Groupe Tumeurs Digestives of the Federation Narionale des Centres de Lutte Contre le Cancer study. J. Clin. Oncol. (2005) 23(6):1228-1236.
10. WELLS A: EGF receptor. Int. J. Biochem. Cell Biol. (1999) 31(6):637-643.
11. ARTEAGA CL: The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J. Clin. Oncol. (2001) 19(18 Suppl.):32S-40S.
12. YARDEN Y, SLIWKOWSKI MX: Untangling the ErbB signaling network. Nat. Rev. Mol. Cell. Biol. (2001) 2(2):127-137.
13. MOTOYAMA AB, HYNES NE, LANE HA: The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides. Cancer Res. (2002) 62(11):3151-3158.
14. FRIEDLANDER E, ARNDT-JOVIN DJ, NAGY P, JOVIN TM, SZOLLOSI J, VEREB G: Signal transduction of erbB receptors in trastuzumab (Herceptin) sensitive and resistant cell lines: local stimulation using magnetic microspheres as assessed by quantitative digital microscopy. Cytometry A. (2005) 67(2):161-171.
15. XIONG HQ, ABBRUZZESE JL: Epidermal growth factor receptor-targeted therapy for pancreatic cancer. Semin. Oncol. (2002) 29:31-37.
16. LEMOINE NR, HUGHES CM, BARTON CM et al.: The epidermal growth factor receptor in human pancreatic cancer. J. Pathol. (1992) 166(1):7-12.
17. YAMANAKA Y, FRIESS H, KOBRIN MS et al.: Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anti-Cancer Res. (1993) 13(3):565-569.
18. DONG M, NIO Y, GUO KJ et al.: Epidermal growth factor and its receptor as prognostic indicators in Chinese patients with pancreatic cancer. Anti-Cancer Res. (1998) 18(6B):4613-4619.
19. YARDEN Y: The EGFR family and its ligands in human cancer: signaling mechanisms and therapeutic opportunities. Eur. J. Cancer. (2001) 37(Suppl. 4):S3-S8.
20. CRAVEN RJ, LIGHTFOOT H, CANCE WG: A decade of tyrosine kinases: from gene discovery to therapeutics. Surg. Oncol. (2003) 12(1):39-49.
21. LEVITZKI A: Protein tyrosine kinase inhibitors as novel therapeutic agents. Pharmacol. Ther. (1999) 82(2-3):231-239.
22. OSHEROV N, LEVITZKI A: Epidermal-growth-factor-dependent activation of the src-family kinases. Eur. J. Biochem. (1994) 225(3):1047-1053.
23. MENDELSOHN J, BASELGA J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J. Clin. Oncol. (2003) 21(14):2787-2799.
24. NORMANNO N, BIANCO C, DE LUCA A, MAIELLO MR, SALOMON DS: Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment. Endocr. Relat. Cancer (2003) 10(1):1-21.
25. IWATA K, PROVONCHA K, GIBSON N: Inhibition of mutant EGFRvIII transformed cells by tyrosine kinase inhibitor OSI-774 (Tarceva). Proc. Am. Soc. Clin. Oncol. (2002):Abstract 79.
26. MOYER JD, BARBACCI EG, IWATA KK et al.: Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. (1997) 57(21):4838-4848.
27. SOULIERES D, SENZER NN, VOKES EE, HIDALGO M, AGARWALA SS, SIU LL: Multicenter Phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J. Clin. Oncol. (2004) 22(1):77-85.
28. HIDALGO M: Erlotinib: preclinical investigations. Oncology (2003) 17(11 Suppl. 12): 11-16.
29. DURKIN AJ, OSBORNE DA, YEATMAN TJ, ROSEMURGY AS, ARMSTRONG C, ZERVOS EE: EGF receptor antagonism improves survival in a murine model of pancreatic adenocarcinoma. J. Surg. Res. (2006) 135(1):195-201
30. DURKIN AJ, BLOOMSTON PM, ROSEMURGY AS et al.: Defining the role of the epidermal growth factor receptor in pancreatic cancer grown in vitro. Am. J. Surg. (2003) 186(5):431-436.
31. NG SS, TSAO MS, NICKLEE T et al.: Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol. Cancer Ther. (2002) 1(10):777-783.
32. MOORE MR: Brief communication: a new combination in the treatment of advanced pancreatic cancer. Semin. Oncol. (2005) 32(6 Suppl. 8):5-6.
33. MOORE MJ, GOLDSTIN D, HAMM J et al.: Erlotinib improves survival when added to gemcitabine in patients with advanced pancreatic cancer. A Phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. Proc. Am. Soc. Clin. Oncol. Gastrointestinal Cancers Symposium (2005):Abstract 77.
34. SHEPHERD FA, RODRIGUES PJ, CIULEANU T et al.:Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. (2005) 353(2):123-132.
35. HERBST RS, PRAGER D, HERMANN R et al.: TRIBUTE - A Phase III trial of erlotinib HCl (OSI-774) combined with carboplatin and paclitaxel (CP) chemotherapy in advanced non-small cell lung cancer (NSCLC). J. Clin. Oncol. (2005) 23(25):5892-5899.
36. GATZEMEIER U, PLUZANSKA A, SZCZESNA A et al.: Results of a Phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). J. Clin. Oncol. 2004 ASCO Ann. Meet. Proc. (Post-Meeting Edn) (2004) 22(14S):7010.
37. CHINNAIYAN S, HUANG S, ARMSTRONG E et al.: Radiosensitization following EGFR signaling inhibition by erlotinib (Tarceva). Int. J. Rad. Onc. Biol. Phys. (2003) 57(Suppl. 1):S294.
38. CONTESSA JN, ABELL A,VALERIE K, LIN PS, SCHMIDT-ULLRICH RK: ErbB receptor tyrosine kinase network inhibition radiosensitizes carcinoma cells. Int. J. Radiat. Oncol. Biol. Phys. (2006) 65(3):851-858.
39. HARARI P, HUANG SM: Combining EGFR inhibitors with radiation or chemotherapy: will preclinical studies predict clinical results? Int. J. Radiat. Oncol. Biol. Phys. (2004) 58(3):976-983.
40. IANNITTI D, DIPETRILLO T, AKERMAN P et al.: Erlotinib and chemoradiation followed by maintenance erlotinib for locally advanced pancreatic cancer: a Phase I study. Am. J. Clin. Oncol. (2005) 28(6):570-575.
41. KORTMANSKY JS, O'REILLY EM, MINSKY BD et al.: A Phase I trial of erlotinib, gemcitabine and radiation for patients with locally-advanced, unresectable pancreatic cancer. J. Clin. Oncol. 2005 ASCO Ann. Meet. Proc. (2005) 23(16S):4107.
42. CIARDELLO F, CAPUTO K, BIANCO R et al.: Antitumor effect and potenation of cytotoxic drugs activity in hyman cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin. Cancer Res. (2000) 6:2053-2063.
43. RABEN D, HELFRICH B, CHANS D et al.: ZD1839, a selective epidermal growth factor tyrosine kinase inhibitor enhances radiation induced cytotoxicty in human pancreatic and cholangiocarcinoma cell lines in vitro. Presented at the Gastrointestinal Cancer Research Conference, Orlando FL, USA, November 2000.
44. HERBST RS, MADDOW AM, ROTHENBERG ML et al.: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a Phase I trial. J. Clin. Oncol. (2002) 20:3815-3825.
45. CZITO BG, WILLETT CG, BENDELL JC et al.: Increased toxicity with gefitinib, capecitabine and radiation therapy in pancreatic and rectal cancer: Phase I trial results. J. Clin. Oncol. (2006) 24:656-662.
46. MAUREL J, MARTIN-RICHARD M, CONILL C et al.: Phase I trial of gefitinib with concurrent radiotherapy and fixed 2-h gemcitabine infusion in locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. (2006) 66:1391-1398.
47. CHEN H, RABEN D, SCHEFTER T et al.: KRAS mutation analysis in patients with locally advanced pancreatic cancer (LAPC) treated with gefitinib and chemoradiation therapy (CT-RT) in a Phase I trial. J. Clin. Oncol. 2006 ASCO Ann. Meet. Proc. Part I. (2006) 24(18S):4106.
48. GIACCONE G, HERBST RS, MANEGOLD C et al.: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a Phase III trial - Intact 1. J. Clin. Oncol. (2004) 22:777-784.
49. HERBST RS, GIACCONE G, SCHILLER JH et al.: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a Phase III trial - intact 2. J. Clin. Oncol. (2004) 22:785-794.
50. GRUNWALD V, HIDALGO M: Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J. Natl. Cancer Inst. (2003)95(12):851-867.
51. WISSNER A, BRAWNER F, RABINDRAN SK, NILAKANTAN R et al.: Syntheses and EGFR and HER-2 kinase inhibitory activities of 4-anilinoquinoline-3-carbonitiriles: analogues of three important 4-anilinoquinazolines currently undergoing clinical evaluation as therapeutic antitumor agents. Bioorg. Med. Chem. Lett. (2002) 12(20):2893-2897.
52. ERLICHMAN C, HIDALGO M, BONI et al.: Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J. Clin. Oncol. (2002) 24(115):2225-2226.
53. MORGAN JA, BUKOWSKI RM, XIONG H et al.: Preliminary report of a Phase I study of EKB-569, an irreversitble inhibitor of the epidermal growth factor receptor (EGFR) given in combination with gemcitabine to patients with advanced pancreatic cancer. Proc. Am. Soc. Clin. Oncol. (2003) 22:197 (Abstract 788).
54. XIA W, MULLIN RJ, KEITH BR et al.: Anti-tumor activity of lapatinib: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erB2 and downstream Erk1/2 and AKT pathways. Oncogene (2002) 21:6255-6263.
55. GRAUS-PORTA D, BEERLI RR, DALY JM et al.: ErbB2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO (1997) 16:1647-1655.
56. RUSNAK DW, LACKEY K, AFFLECK K et al.: The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, lapatinib, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol. Cancer Ther. (2001) 1:85-94.
57. BURGESS AW, CHO HS, EIGENBROT C et al.: An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell (2003) 12:541-552.
58. ASANO T, YAO Y, ZHU J et al.: The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells. Oncogene (2004) 23:8571-8580.
59. SAFRAN H, IANNITTI D, MINER T et al.: GW572016, gemcitabine and GW572016, gemcitabine, oxaliplatin, a two-stage, Phase I study for advanced pancreaticobiliary cancer. Proc. Am. Soc. Clin. Oncol. (2006) 24: 179s (Abstract 4002).
60. BRUNS CJ, HARBISON MT, DAVIS DW et al.: Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin. Cancer Res. (2000) 6(5):1936-1948.
61. OVERHOLSER JP, PREWETT MC, HOOPER AT et al.: Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice. Cancer (2000) 89(1):74-82.
62. HUANG ZQ, BUCHSBAUM DJ, RAISCH KP et al.: Differential responses by pancreatic carcinoma cell lines to prolonged exposure to Erbitux (IMC-C225) anti-EGFR antibody. J. Surg. Res. (2003) 111(2):274-283.
63. ARNOLETTI JP, BUCHSBAUM DJ, HUANG ZQ et al.: Mechanisms of resistance to Erbitux (anti-epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells. J. Gastrointest. Surg. (2004) 8(8):960-969.
64. SCLABAS GM, FUJIOKA S, SCHMIDT S et al.: Restoring apoptosis in pancreatic cancer cells by targeting the nuclear factor-kappaB signaling pathway with the anti-epidermal growth factor antibody IMC-C225. J. Gastrointest. Surg. (2003) 7(1):37-43.
65. XIONG HQ, ROSENBERG A, LOBUGLIO A et al.: Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter Phase II trial. J. Clin. Oncol. (2004)22(13):2610-2616.
66. LAMMERING G: Inhibition of the Type III epidermal growth factor receptor variant mutant receptor by dominant-negative EGFR-CD533 enhances malignant glioma cell radiosensitivity. Clin. Cancer Res. (2004) 10(19):6732-6743.
67. JENSEN AD, MUSCHER MW, BISCHOFF H et al.: Treatment of non-small cell lung cancer with intensity-modulated radiation therapy in combination with cetuximab: the NEAR protocol (NCT00115518). BMC Cancer (2006) 6(1):122.
68. BAUMANN M, KRAUSE M: Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results. Radiother. Oncol. (2004) 72(3):257-266.
69. BONNER JA, HARARI PM, GIRALT J et al.: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N. Engl. J. Med. (2006) 354(6):567-578.
70. BOWERS G, REARDON D, HEWITT T et al.: The relative role of ErbB 1-4 receptor tyrosine kinases in radiation signal transduction responses of human carcinoma cells. Oncogene (2001) 20(11):1388-1397.
71. RABEN D, HELFRICH B, CHAN DC et al.: The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin. Cancer Res. (2005) 11(2 Pt 1):795-805.
72. KRAUSE C, SCHUTZE M, PETERSEN M: Different classes of EGFR inhibitors may have different potential to improve local tumour control after fractionated irradiation: a study on C225 in FaDu hSCC. Radiother. Oncol. (2005) 74(2):109-115.
73. LAMMERING G, VALERIE K, LIN PS et al.: Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance. Radiother. Oncol. (2004) 72(3):267-273.
74. DENT P, REARDON DB, PARK JS et al.: Radiation-induced release of transforming growth factor alpha activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death. Mol. Biol. Cell. (1999) 10(8):2493-506.
75. TODD TG, MIKKELSEN RB, RORRER WK et al.: Ionizing radiation stimulates existing signal transduction pathways involving the activation of epidermal growth factor receptor and ERBB-3, and changes of intracellular calcium in A431 human squamous carcinoma cells. J. Recept. Signal Transduct. Res. (1999) 19(6):885-908.
76. SCHMIDT-ULLRICH RK, MIKKELSEN RB, DENT P et al.: Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene (1997) 15(10):1191-1197.
77. HUANG SM, HARARI PM: Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clin. Cancer Res. (2000) 6(6):2166-2174.
78. KETTLEBOROUGH CA, SALDANHA J, HEATH VJ, MORRISON CJ, BENDIG MM: Humanization of a mouse monoclonal antibody by CDR-grafting: the importance of framework residues on loop conformation. Protein Eng. (1991) 4:773-783.
79. BANGARD C, GOSSMANN A, PAPYAN A et al.: Magnetic resonance imaging in an orthotopic rat model: blockade of epidermal growth factor receptor with EMD72000 inhibits human pancreatic carcinoma growth. Int. J. Cancer (2005) 114(1):131-138.
80. BURGER AM, HEISS NS, KREYSCH HG et al.: The humanized monoclonal anti-EGFR antibody EMD72000 potently inhibits the growth of EGFR-expressing human tumor xenografts insensitive to chemotherapeutic drugs [abstract]. Proc. Am. Assoc. Cancer Res. (2002) 44:1139.
81. AMENDT C, MANTELL O, PETERS M et al.: In vivo activity of humanized monoclonal anti-EGFR antibody EMD72000 in combination with gemcitabine on growth of primary pancreatic tumors and metastases in an orthotopic nude mouse model [abstract]. Proc. Am. Assoc. Cancer Res. (2003) 44(2):1234.
82. VANHOEFER U, TEWES M, ROJO F et al.: Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J. Clin. Oncol. (2004) 22(1):175-184.
83. GRAEVEN U, KREMER B, SUEDHOFF TH et al.: Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer. Br. J. Cancer (2006) 94:1293-1299.
84. YANG XD, JIA XC, CORVALAN JC et al.: Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit. Rev. Oncol. Hematol. (2001) 38:17-23.
85. FOON KA, YANG XD, WEINER LM et al.: Preclinical and clinical evaluations of ABX-EGF, a fully human anti-epidermal growth factor receptor antibody. Int. J. Radiat. Oncol. Biol. Phys. (2004) 58(3):984-990.
86. LYNCH DH, YANG XD: Therapeutic potential of ABX-EGF: A fully human anti-epidermal growth factor receptor monoclonal antibody for cancer treatment. Semin. Oncol. (2002) 29(1 Suppl. 4):47-50.
87. JIA XC, CORVALAN JRF, ZHANG L et al.: Inhibition of vascular endothelial cell growth factor and interleukin-8 production in tumor and endothelial cell lines by a fully human monoclonal antibody to epidermal growth factor receptor. Proc. Ann. Meet. Am. Assoc. Cancer Res. (2000):290.
88. FIGLIN RA, BELLDEGRUN AS, CRAWFORD J et al.: ABX-EGF, a fully human anti-epideral growth factor receptor (EGFR) monoclonal antibody (mAb) in patients with advanced cancer: Phase I clinical results. Proc. Am. Soc. Clin. Oncol. (2002) 21:Abstract 35.
89. YAMANAKA Y, FRIESS H, KOBRIN MS et al.: Overexpression of HER-2/neu oncogene in human pancreatic carcinoma. Hum. Pathol. (1993) 24(10):1127-1134.
90. HALL PA, HUGHES CM, STADDON SL et al.: The c-erbB-2 proto-oncogene in human pancreatic cancer. J. Pathol. (1990) 161(3):195-200.
91. SATOH K, SASANO H, SHIMOSEGAWA T et al.: An immunohistochemical study of the c-erbB-2 oncogene product in intraductal mucin- hypersecreting neoplasms and in ductal cell carcinomas of the pancreas. Cancer (1993) 72(1):51-56.
92. LEI S, APPERT SE, NAKATA B et al.: Overexpression of HER-2/neu oncogene in pancreatic cancer correlates with shortened survival. Int. J. Pancreatol. (1995) 17:15-21.
93. SAFRAN H, STEINHOFF M, MANGRAY S et al.: Overexpression of the HER-2/neu oncogene in pancreatic adenocarcinoma. Am. J. Clin. Oncol. (2001) 24:496-499.
94. SAFRAN H, IANNITTI D, RAMANATHAN R et al.: Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest. (2004) 22(5):706-712.
95. LYNCH TJ, BELL DW, SORDELLA R et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. (2004) 350:2129-2139.
96. PAEZ JG, JANNE PA, LEE JC et al.: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (2004) 304:1497-1500.
97. RAYMOND E, FAIVRE S, ARMAND JP: Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs (2000) 60(Suppl. 1):15-23.
98. 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 (2004) 101:13306.
99. TOKUMO M, TOYOOKA S, KIURA K et al.: The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin. Cancer Res. (2005) 11(3):1167.
100. KWAK E, JANKOWSKI J, THAYER SP et al.: Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin. Cancer Res. (2006) 12(14 Pt 1):4283-4287.
101. IMMERVOLL H, HOEM D, KUGARADJH K, STEINE SJ, MOLVEN A: Molecular analysis of the EGFR-RAS-RAF pathway in pancreatic ductal adenocarcinomas: lack of mutations in the BRAF and EGFR genes. Virchows Arch. (2006) 448(6):788-796.
102. EBERHARD DA, JOHNSON BE, AMLER LC et al.: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. (2005) 23(25):5900-5909.
103. AVIEL-RONEN S, FIONA H, BLACKHALL FH, SHEPHERD FA, TSAO MS: K-ras Mutations in non-small-cell lung carcinoma: a review. Clin. Lung Cancer (2006) 8(1):30-38.
104. LOHR M, KLOPPEL G, MAISONNEUVE P, LOWENFELS AB, LUTTGES J: Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia (2005) 7:17-23.
105. HRUBAN RH, GOGGINS M, PARSONS J, KERN SE: Progression model for pancreatic cancer. Clin. Cancer Res. (2000) 6(8):2969-2972.
106. ROZENBLUM E, SCHUTTE M, GOGGINS M et al.: Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. (1997) 57:1731-1734.
107. BIANCO R, SHIN I, RITTER C et al.: Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene (2003) 22(18):2812-2822.
108. VAZQUEZ F, SELLER WR: The PTEN tumor suppressor protein: an antagonist of phosphor-inositide 3-kinase signaling. Biochem. Biophys. Acta (2000) 1470:M21-M35.
109. MELLINGHOFF I, WANG M, VIVANCO I et al.: Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. (2005) 353(19):2012-2024.