Home LiteratureArticle Details
PMID: 20551942 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Understanding resistance to EGFR inhibitors-impact on future treatment strategies.

Nature reviews. Clinical oncology ·Vol. 7 ·No. 9 ·2010-09-00 ·Pages 493-507

Wheeler DL, Dunn EF, Harari PM

Abstract

EGFR is a tyrosine kinase that participates in the regulation of cellular homeostasis. Following ligand binding, EGFR stimulates downstream cell signaling cascades that influence cell proliferation, apoptosis, migration, survival and complex processes, including angiogenesis and tumorigenesis. EGFR has been strongly implicated in the biology of human epithelial malignancies, with therapeutic applications in cancers of the colon, head and neck, lung, and pancreas. Accordingly, targeting EGFR has been intensely pursued, with the development of a series of promising molecular inhibitors for use in clinical oncology. As is common in cancer therapy, challenges with respect to treatment resistance emerge over time. This situation is certainly true of EGFR inhibitor therapies, where intrinsic and acquired resistance is now well recognized. In this Review, we provide a brief overview regarding the biology of EGFR, preclinical and clinical development of EGFR inhibitors, and molecular mechanisms that underlie the development of treatment resistance. A greater understanding of the mechanisms that lead to EGFR resistance may provide valuable insights to help design new strategies that will enhance the impact of this promising class of inhibitors for the treatment of cancer.

MeSH Terms
Antibodies, Monoclonal/therapeutic use Antibodies, Monoclonal, Humanized Antineoplastic Agents/therapeutic use Cetuximab Disease Progression Drug Resistance, Neoplasm ErbB Receptors/antagonists & inhibitors,metabolism Erlotinib Hydrochloride Gefitinib Humans Neoplasms/drug therapy,genetics Panitumumab Protein Kinase Inhibitors/pharmacology,therapeutic use Proto-Oncogene Proteins/genetics Proto-Oncogene Proteins p21(ras) Quinazolines/therapeutic use Treatment Outcome ras Proteins/genetics
Chemicals
Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antineoplastic Agents KRAS protein, human Protein Kinase Inhibitors Proto-Oncogene Proteins Quinazolines Panitumumab Erlotinib Hydrochloride ErbB Receptors Proto-Oncogene Proteins p21(ras) ras Proteins Cetuximab Gefitinib
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Wheeler Deric L
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison, WI 53705, USA. dlwheeler@wisc.edu
Dunn Emily F
Harari Paul M
References (175)
175 references, click to expand
  1. Amplification and overexpression of the EGF receptor gene in primary human glioblastomas.
    J Cell Sci Suppl. 1985;3:161-72 PMID: 3011820
  2. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells.
    Clin Cancer Res. 2006 Jul 1;12(13):4103-11 PMID: 16818711
  3. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099.
    J Clin Oncol. 2010 Feb 20;28(6):911-7 PMID: 20100966
  4. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations.
    Br J Cancer. 2006 Oct 23;95(8):998-1004 PMID: 17047648
  5. Erlotinib in previously treated non-small-cell lung cancer.
    N Engl J Med. 2005 Jul 14;353(2):123-32 PMID: 16014882
  6. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP.
    Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2070-5 PMID: 18227510
  7. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck.
    Cancer Res. 1999 Apr 15;59(8):1935-40 PMID: 10213503
  8. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study.
    J Clin Oncol. 2005 Dec 1;23(34):8646-54 PMID: 16314626
  9. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors.
    Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4995-5000 PMID: 10220407
  10. Functional nuclear epidermal growth factor receptors in human choriocarcinoma JEG-3 cells and normal human placenta.
    Endocrinology. 1995 Jul;136(7):3163-72 PMID: 7540549
  11. Nuclear EGFR contributes to acquired resistance to cetuximab.
    Oncogene. 2009 Oct 29;28(43):3801-13 PMID: 19684613
  12. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody.
    Proc Natl Acad Sci U S A. 1983 Mar;80(5):1337-41 PMID: 6298788
  13. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation.
    Clin Cancer Res. 2002 May;8(5):1178-84 PMID: 12006535
  14. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin.
    Nature. 1985 Jan 10-18;313(5998):144-7 PMID: 2981413
  15. Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer.
    Cancer Res. 2005 Jan 1;65(1):338-48 PMID: 15665312
  16. Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer.
    J Clin Oncol. 2005 Dec 1;23(34):8786-93 PMID: 16246975
  17. Nuclear expression of epidermal growth factor receptor is a novel prognostic value in patients with ovarian cancer.
    Mol Carcinog. 2009 Jul;48(7):610-7 PMID: 19058255
  18. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling.
    Cancer Res. 2002 Jan 1;62(1):200-7 PMID: 11782378
  19. Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer.
    Cancer Cell. 2006 Jul;10(1):39-50 PMID: 16843264
  20. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function.
    J Biol Chem. 1999 Mar 19;274(12):8335-43 PMID: 10075741
  21. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.
    Cancer. 2001 Sep 15;92(6):1525-30 PMID: 11745231
  22. K-ras mutations and benefit from cetuximab in advanced colorectal cancer.
    N Engl J Med. 2008 Oct 23;359(17):1757-65 PMID: 18946061
  23. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.
    JAMA. 2003 Oct 22;290(16):2149-58 PMID: 14570950
  24. Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme.
    Clin Cancer Res. 2004 May 1;10(9):3216-24 PMID: 15131063
  25. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor.
    Cell. 1993 May 7;73(3):611-20 PMID: 8490966
  26. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing.
    Cell. 1987 Oct 23;51(2):199-209 PMID: 3499230
  27. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine.
    Proc Natl Acad Sci U S A. 1980 Mar;77(3):1311-5 PMID: 6246487
  28. Identification of residues in the nucleotide binding site of the epidermal growth factor receptor/kinase.
    J Biol Chem. 1985 May 10;260(9):5205-8 PMID: 2985580
  29. Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation.
    Exp Cell Res. 2004 Nov 1;300(2):388-95 PMID: 15475003
  30. ERBB receptors and cancer: the complexity of targeted inhibitors.
    Nat Rev Cancer. 2005 May;5(5):341-54 PMID: 15864276
  31. Insulin and insulin-like growth factor signalling in neoplasia.
    Nat Rev Cancer. 2008 Dec;8(12):915-28 PMID: 19029956
  32. Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer.
    Clin Ther. 2005 Jun;27(6):684-94 PMID: 16117976
  33. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas.
    Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4283-7 PMID: 16857803
  34. Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFR-STAT3 and EGFRvIII-STAT3 signaling axes.
    Mol Cancer Res. 2010 Feb;8(2):232-45 PMID: 20145033
  35. Antibodies to the ATP-binding site of the human epidermal growth factor (EGF) receptor as specific inhibitors of EGF-stimulated protein-tyrosine kinase activity.
    Eur J Biochem. 1986 Jul 15;158(2):245-53 PMID: 3015611
  36. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling.
    Clin Cancer Res. 2003 Oct 1;9(12):4340-6 PMID: 14555504
  37. Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines.
    Breast Cancer Res Treat. 1996;38(1):67-73 PMID: 8825124
  38. Phosphotyrosine 1173 mediates binding of the protein-tyrosine phosphatase SHP-1 to the epidermal growth factor receptor and attenuation of receptor signaling.
    J Biol Chem. 1998 Sep 18;273(38):24839-46 PMID: 9733788
  39. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis.
    Cancer Res. 2001 Jul 1;61(13):5090-101 PMID: 11431346
  40. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab.
    Cancer Cell. 2005 Apr;7(4):301-11 PMID: 15837620
  41. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer.
    J Clin Oncol. 2008 May 10;26(14):2311-9 PMID: 18390971
  42. Untangling the ErbB signalling network.
    Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37 PMID: 11252954
  43. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.
    J Clin Oncol. 2008 Apr 1;26(10):1626-34 PMID: 18316791
  44. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck.
    J Clin Oncol. 2005 Aug 20;23(24):5578-87 PMID: 16009949
  45. 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. 2007 May 20;25(15):1960-6 PMID: 17452677
  46. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.
    J Clin Oncol. 2010 Jan 10;28(2):357-60 PMID: 19949011
  47. Cetuximab for the treatment of colorectal cancer.
    N Engl J Med. 2007 Nov 15;357(20):2040-8 PMID: 18003960
  48. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial.
    J Clin Oncol. 2007 Apr 20;25(12):1545-52 PMID: 17442998
  49. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines.
    Clin Cancer Res. 2007 Mar 1;13(5):1552-61 PMID: 17332301
  50. Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer.
    J Clin Oncol. 2005 Dec 20;23(36):9089-96 PMID: 16301597
  51. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy.
    J Clin Oncol. 2009 Mar 20;27(9):1394-400 PMID: 19224850
  52. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.
    Cancer Res. 2006 Apr 15;66(8):3992-5 PMID: 16618717
  53. The EGFR as a target for anticancer therapy--focus on cetuximab.
    Eur J Cancer. 2001 Sep;37 Suppl 4:S16-22 PMID: 11597400
  54. Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1.
    J Cell Biochem. 2006 Aug 15;98(6):1570-83 PMID: 16552725
  55. Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity.
    Radiother Oncol. 2005 Aug;76(2):157-61 PMID: 16024112
  56. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy.
    Crit Rev Oncol Hematol. 2001 Apr;38(1):17-23 PMID: 11255078
  57. The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells.
    Cancer Res. 2001 Oct 1;61(19):7184-8 PMID: 11585753
  58. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected].
    J Clin Oncol. 2003 Jun 15;21(12):2237-46 PMID: 12748244
  59. Signal transduction and oncogenesis by ErbB/HER receptors.
    Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):903-13 PMID: 14967450
  60. Epidermal-growth-factor-dependent activation of the src-family kinases.
    Eur J Biochem. 1994 Nov 1;225(3):1047-53 PMID: 7525285
  61. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer.
    J Clin Oncol. 2009 Feb 10;27(5):672-80 PMID: 19114685
  62. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR.
    Nat Genet. 2005 Dec;37(12):1315-6 PMID: 16258541
  63. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib.
    Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11 PMID: 15329413
  64. Platinum-based chemotherapy plus cetuximab in head and neck cancer.
    N Engl J Med. 2008 Sep 11;359(11):1116-27 PMID: 18784101
  65. Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity.
    Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8132-6 PMID: 8058768
  66. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase.
    Science. 1994 Aug 19;265(5175):1093-5 PMID: 8066447
  67. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3.
    Nat Rev Cancer. 2009 Jul;9(7):463-75 PMID: 19536107
  68. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy.
    Cancer Res. 1999 Mar 15;59(6):1236-43 PMID: 10096554
  69. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor.
    Clin Cancer Res. 2001 May;7(5):1459-65 PMID: 11350918
  70. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer.
    J Thorac Oncol. 2007 Jan;2(1):22-8 PMID: 17410005
  71. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations.
    J Natl Cancer Inst. 2005 Aug 17;97(16):1185-94 PMID: 16106023
  72. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells.
    Nature. 1984 May 31-Jun 6;309(5967):418-25 PMID: 6328312
  73. Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression.
    Mol Biol Cell. 2007 Mar;18(3):1064-72 PMID: 17215517
  74. Anti-oncogenic activity of signalling-defective epidermal growth factor receptor mutants.
    Mol Cell Biol. 1992 Feb;12(2):491-8 PMID: 1346334
  75. Screening for epidermal growth factor receptor mutations in lung cancer.
    N Engl J Med. 2009 Sep 3;361(10):958-67 PMID: 19692684
  76. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins.
    J Clin Invest. 2008 Jul;118(7):2609-19 PMID: 18568074
  77. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors.
    Oncogene. 2003 May 8;22(18):2812-22 PMID: 12743604
  78. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study.
    J Clin Oncol. 2007 Oct 10;25(29):4557-61 PMID: 17876013
  79. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.
    PLoS Med. 2005 Jan;2(1):e17 PMID: 15696205
  80. ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent.
    Cancer Res. 1991 Sep 15;51(18):4999-5002 PMID: 1654209
  81. K-ras mutations in human adenocarcinoma of the lung: association with smoking and occupational exposure to asbestos.
    Int J Cancer. 1993 Jan 21;53(2):250-6 PMID: 8425762
  82. Combined epidermal growth factor receptor targeting with the tyrosine kinase inhibitor gefitinib (ZD1839) and the monoclonal antibody cetuximab (IMC-C225): superiority over single-agent receptor targeting.
    Clin Cancer Res. 2004 Oct 1;10(19):6487-501 PMID: 15475436
  83. Survival of cancer cells is maintained by EGFR independent of its kinase activity.
    Cancer Cell. 2008 May;13(5):385-93 PMID: 18455122
  84. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells.
    Cancer Res. 2008 Apr 1;68(7):2391-9 PMID: 18381447
  85. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth.
    Ann Oncol. 2002 Jan;13(1):65-72 PMID: 11863114
  86. EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization.
    Breast Cancer Res Treat. 2006 Feb;95(3):211-8 PMID: 16261406
  87. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer.
    J Clin Oncol. 2005 Sep 1;23(25):5892-9 PMID: 16043829
  88. EGFR mutation conferring primary resistance to gefitinib in non-small-cell lung cancer.
    N Engl J Med. 2005 Jul 14;353(2):207-8 PMID: 16014893
  89. Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity.
    Br J Cancer. 2000 Jun;82(12):1991-9 PMID: 10864208
  90. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines.
    J Clin Oncol. 2006 Oct 20;24(30):4914-21 PMID: 17050875
  91. Amphiregulin and epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with cetuximab.
    J Clin Oncol. 2009 Oct 20;27(30):5068-74 PMID: 19738126
  92. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.
    J Clin Oncol. 2007 May 1;25(13):1658-64 PMID: 17470858
  93. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2.
    J Clin Oncol. 2004 Mar 1;22(5):785-94 PMID: 14990633
  94. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.
    N Engl J Med. 2005 Feb 24;352(8):786-92 PMID: 15728811
  95. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy.
    J Clin Oncol. 2009 Apr 20;27(12):2091-6 PMID: 19188670
  96. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy.
    Clin Cancer Res. 2004 Jan 15;10(2):784-93 PMID: 14760102
  97. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab.
    J Clin Oncol. 2007 Aug 1;25(22):3230-7 PMID: 17664471
  98. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy.
    Br J Cancer. 2007 Apr 23;96(8):1166-9 PMID: 17375050
  99. Phase I study of anti--epidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer.
    J Clin Oncol. 2001 Jul 1;19(13):3234-43 PMID: 11432891
  100. Radiation-induced caveolin-1 associated EGFR internalization is linked with nuclear EGFR transport and activation of DNA-PK.
    Mol Cancer. 2008 Sep 12;7:69 PMID: 18789131
  101. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members.
    Oncogene. 2008 Jun 26;27(28):3944-56 PMID: 18297114
  102. Nuclear epidermal growth factor receptor (EGFR) interacts with signal transducer and activator of transcription 5 (STAT5) in activating Aurora-A gene expression.
    Nucleic Acids Res. 2008 Aug;36(13):4337-51 PMID: 18586824
  103. Acquired gefitinib-resistant mutation of EGFR in a chemonaive lung adenocarcinoma harboring gefitinib-sensitive mutation L858R.
    PLoS Med. 2005 Sep;2(9):e269 PMID: 16173832
  104. 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. 2005 Oct 29-Nov 4;366(9496):1527-37 PMID: 16257339
  105. Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor.
    Cancer Res. 2004 Aug 1;64(15):5355-62 PMID: 15289342
  106. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab.
    J Clin Oncol. 2007 Aug 1;25(22):3238-45 PMID: 17664472
  107. Mammary-derived growth inhibitor alters traffic of EGFR and induces a novel form of cetuximab resistance.
    Clin Cancer Res. 2009 Nov 1;15(21):6570-81 PMID: 19825952
  108. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations.
    J Clin Oncol. 2008 May 20;26(15):2442-9 PMID: 18458038
  109. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer.
    Ann Oncol. 2008 Feb;19(2):362-9 PMID: 17947225
  110. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.
    N Engl J Med. 2009 Apr 2;360(14):1408-17 PMID: 19339720
  111. Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival.
    Br J Cancer. 2006 Jan 30;94(2):184-8 PMID: 16434982
  112. Mutational activation of the K-ras oncogene. A possible pathogenetic factor in adenocarcinoma of the lung.
    N Engl J Med. 1987 Oct 8;317(15):929-35 PMID: 3041218
  113. Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ('Iressa') is independent of EGFR expression level.
    J Cell Physiol. 2004 Feb;198(2):259-68 PMID: 14603528
  114. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo.
    Cancer Res. 2001 Dec 15;61(24):8887-95 PMID: 11751413
  115. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
    Science. 2004 Jun 4;304(5676):1497-500 PMID: 15118125
  116. Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis.
    Clin Cancer Res. 2005 Aug 15;11(16):5856-62 PMID: 16115926
  117. Insulin-like growth factor receptor 1 (IGFR-1) is significantly associated with longer survival in non-small-cell lung cancer patients treated with gefitinib.
    Ann Oncol. 2006 Jul;17(7):1120-7 PMID: 16600976
  118. Characterization of the binding of 125-I-labeled epidermal growth factor to human fibroblasts.
    J Biol Chem. 1975 Jun 10;250(11):4297-304 PMID: 1126952
  119. Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers.
    Genes Chromosomes Cancer. 1998 Jun;22(2):152-6 PMID: 9598803
  120. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors.
    Mol Biol Med. 1983 Dec;1(5):511-29 PMID: 6094961
  121. Co-regulation of B-Myb expression by E2F1 and EGF receptor.
    Mol Carcinog. 2006 Jan;45(1):10-7 PMID: 16299810
  122. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal.
    J Biol Chem. 1962 May;237:1555-62 PMID: 13880319
  123. Lapatinib plus capecitabine for HER2-positive advanced breast cancer.
    N Engl J Med. 2006 Dec 28;355(26):2733-43 PMID: 17192538
  124. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck.
    J Clin Oncol. 2005 Aug 20;23(24):5568-77 PMID: 16009950
  125. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model.
    Clin Cancer Res. 1995 Nov;1(11):1311-8 PMID: 9815926
  126. EGFR and KRAS mutations as criteria for treatment with tyrosine kinase inhibitors: retro- and prospective observations in non-small-cell lung cancer.
    Ann Oncol. 2007 Jan;18(1):99-103 PMID: 17060486
  127. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations.
    J Clin Oncol. 2006 Jul 20;24(21):3340-6 PMID: 16785471
  128. Epidermal growth factor receptor gene amplification and expression in head and neck cancer cell lines.
    Head Neck. 1989 Sep-Oct;11(5):437-42 PMID: 2807884
  129. Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the anti-EGFR monoclonal antibody cetuximab.
    Cancer Res. 2007 Sep 1;67(17):8240-7 PMID: 17804738
  130. The stimulation of epidermal proliferation by a specific protein (EGF).
    Dev Biol. 1965 Dec;12(3):394-407 PMID: 5884352
  131. Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications.
    Cancer Res. 2004 Dec 15;64(24):8919-23 PMID: 15604253
  132. Nuclear localization of EGF receptor and its potential new role as a transcription factor.
    Nat Cell Biol. 2001 Sep;3(9):802-8 PMID: 11533659
  133. Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK.
    Ann Oncol. 2008 Jul;19(7):1288-1292 PMID: 18349029
  134. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway.
    Cancer Cell. 2005 Jun;7(6):575-89 PMID: 15950906
  135. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab.
    Ann Oncol. 2008 Mar;19(3):508-15 PMID: 17998284
  136. Erlotinib directly inhibits HER2 kinase activation and downstream signaling events in intact cells lacking epidermal growth factor receptor expression.
    Cancer Res. 2007 Feb 1;67(3):1228-38 PMID: 17283159
  137. Characterization of a novel tripartite nuclear localization sequence in the EGFR family.
    J Biol Chem. 2007 Apr 6;282(14):10432-40 PMID: 17283074
  138. Localization of epidermal growth factor receptor in hepatocyte nuclei.
    Hepatology. 1991 Jan;13(1):15-20 PMID: 1988335
  139. Signaling-inactive epidermal growth factor receptor/ligand complexes in intact carcinoma cells by quinazoline tyrosine kinase inhibitors.
    Cancer Res. 2001 Aug 1;61(15):5790-5 PMID: 11479217
  140. An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates.
    Cell. 1979 Dec;18(4):925-33 PMID: 229973
  141. Nuclear targeting of Bax during apoptosis in human colorectal cancer cells.
    Oncogene. 1998 Aug 27;17(8):999-1007 PMID: 9747879
  142. U.S. Food and Drug Administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
    Clin Cancer Res. 2008 Mar 1;14(5):1296-302 PMID: 18316547
  143. Tyrosine phosphorylation controls PCNA function through protein stability.
    Nat Cell Biol. 2006 Dec;8(12):1359-68 PMID: 17115032
  144. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene.
    Cell Growth Differ. 1995 Oct;6(10):1251-9 PMID: 8845302
  145. Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro.
    Nature. 1978 Nov 23;276(5686):409-10 PMID: 309559
  146. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study.
    Lancet Oncol. 2005 May;6(5):279-86 PMID: 15863375
  147. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor.
    Cancer Sci. 2007 Aug;98(8):1275-80 PMID: 17498200
  148. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.
    Science. 2007 May 18;316(5827):1039-43 PMID: 17463250
  149. Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas.
    Oncology (Williston Park). 2007 Dec;21(14):1696-706; discussion 1706-9, 1712, 1715 PMID: 18247017
  150. Erlotinib in lung cancer - molecular and clinical predictors of outcome.
    N Engl J Med. 2005 Jul 14;353(2):133-44 PMID: 16014883
  151. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.
    N Engl J Med. 2004 Jul 22;351(4):337-45 PMID: 15269313
  152. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1.
    J Clin Oncol. 2004 Mar 1;22(5):777-84 PMID: 14990632
  153. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.
    PLoS Med. 2005 Mar;2(3):e73 PMID: 15737014
  154. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
    N Engl J Med. 2004 May 20;350(21):2129-39 PMID: 15118073
  155. Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab.
    Cancer Biol Ther. 2009 Apr;8(8):696-703 PMID: 19276677
  156. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry.
    J Clin Oncol. 2005 Mar 20;23(9):1803-10 PMID: 15677699
  157. Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology.
    Mol Biol Cell. 1993 Jan;4(1):121-33 PMID: 7680247
  158. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.
    J Clin Oncol. 2009 Feb 10;27(5):663-71 PMID: 19114683
  159. Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy.
    Clin Exp Immunol. 2009 Oct;158(1):1-9 PMID: 19737224
  160. A mutant epidermal growth factor receptor with defective protein tyrosine kinase is unable to stimulate proto-oncogene expression and DNA synthesis.
    Mol Cell Biol. 1987 Dec;7(12):4568-71 PMID: 3501826
  161. Nuclear translocation of the epidermal growth factor receptor family membrane tyrosine kinase receptors.
    Clin Cancer Res. 2009 Nov 1;15(21):6484-9 PMID: 19861462
  162. More is less -- combining targeted therapies in metastatic colorectal cancer.
    Nat Rev Clin Oncol. 2009 Dec;6(12):731-3 PMID: 19942926
  163. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations.
    Cancer Res. 2008 Nov 15;68(22):9479-87 PMID: 19010923
  164. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines.
    Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3788-93 PMID: 15731348
  165. A novel mechanism of resistance to epidermal growth factor receptor antagonism in vivo.
    Cancer Res. 2007 Jan 15;67(2):665-73 PMID: 17234777
  166. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer.
    J Clin Oncol. 2008 Dec 1;26(34):5544-52 PMID: 18955454
  167. Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer.
    J Clin Oncol. 2007 Dec 20;25(36):5777-84 PMID: 18089875
  168. Expression of epidermal growth factor receptors in human brain tumors.
    Cancer Res. 1984 Feb;44(2):753-60 PMID: 6318976
  169. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting.
    Clin Cancer Res. 2006 Sep 1;12(17):5064-73 PMID: 16951222
  170. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib.
    Proc Natl Acad Sci U S A. 2005 May 24;102(21):7665-70 PMID: 15897464
  171. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.
    N Engl J Med. 2006 Feb 9;354(6):567-78 PMID: 16467544
  172. Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells.
    Clin Cancer Res. 2008 Aug 15;14(16):5069-80 PMID: 18694994
  173. Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3.
    EMBO J. 1995 Sep 1;14(17):4267-75 PMID: 7556068
  174. Epidermal growth factor receptors in non-small cell lung cancer.
    Br J Cancer. 1987 May;55(5):513-6 PMID: 3038157
  175. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial.
    Lancet. 2009 May 2;373(9674):1525-31 PMID: 19410716
Article Info
Journal
Nature reviews. Clinical oncology
Abbr.
Nat Rev Clin Oncol
ISSN
1759-4782
DOI
10.1038/nrclinonc.2010.97
Email
dlwheeler@wisc.edu
Published
2010-09-00
Epub
2010-00-15
Pages
493-507
Language
English
Region
England
NLM ID
101500077
PMCID
PMC2929287
Subset
IM
Grants
NCI NIH HHS · T32 CA009614-20 · United States
NCI NIH HHS · T32 CA009614-12 · United States
NCI NIH HHS · R01 CA113448 · United States
NCI NIH HHS · T32 CA009614-16A1 · United States
NCI NIH HHS · T32 CA009614-15 · United States
NCI NIH HHS · T32 CA009614-10 · United States
NCI NIH HHS · T32 CA009614-17 · United States
NCI NIH HHS · T32 CA009614-18 · United States
NCI NIH HHS · R01 CA113448-02 · United States
NCI NIH HHS · T32 CA009614-13 · United States
NCRR NIH HHS · UL1 RR025011 · United States
NCI NIH HHS · R01 CA113448-03 · United States
NCI NIH HHS · T32 CA009614-19 · United States
NCI NIH HHS · R01 CA113448-01A1 · United States
NCI NIH HHS · T32 CA009614-21 · United States
NCI NIH HHS · T32 CA009614 · United States
NCI NIH HHS · R01 CA113448-05 · United States
NCI NIH HHS · T32 CA009614-14 · United States
NCI NIH HHS · R01 CA113448-04 · United States
PHS HHS · P30CAO14520 · United States
NCI NIH HHS · T32 CA009614-11 · United States
NCI NIH HHS · T32 CA009614-22 · United States
External Links
PubMed source DOI: 10.1038/nrclinonc.2010.97 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2