The Epidermal Growth Factor Receptor Pathway: A Model for Targeted Therapy
Abstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase receptor that is frequently expressed in epithelial tumors. The EGFR was the first receptor to be proposed as a target for cancer therapy, and after 2 decades of intensive research, there are several anti-EGFR agents available in the clinic. Recent advances in our understanding in the mechanisms of receptor activation and function, discovery of primary and secondary EGFR somatic mutations, as well as a new generation of anti-EGFR agents provide new leads on the clinical targeting of this receptor and may serve as a model for strategies aimed at targeting other receptors.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Overexpression or increased activity of wild-type EGFR protein can lead to cell proliferation, migration, survival, and anti-apoptosis through signaling cascades, which are strongly associated with the occurrence and development of many cancers such as NSCLC, breast cancer, glioma, head and neck cancer, cervical cancer, and bladder cancer.
“Overexpression or increased activity of wild-type EGFR protein can lead to cell proliferation, migration, survival, and anti-apoptosis through signaling cascades, which are strongly associated with the occurrence and development of many cancers, such as NSCLC, breast cancer, glioma, head and neck cancer, cervical cancer, and bladder cancer.105–108”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [106]
Cites
Mutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674 · see citing works
<i>EGFR</i> Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368 · see citing works
Untangling the ErbB signalling network
Yarden, Y., & Sliwkowski, M. X. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35052073 · Cited by 6,974 · see citing works
The phosphatidylinositol 3-Kinase–AKT pathway in human cancer
Vivanco, I., & Sawyers, C. L. (2002) · Nature reviews. Cancer · doi:10.1038/nrc839 · Cited by 6,041 · see citing works
Pao, W., Miller, V., Zakowski, M., Doherty, J., Politi, K., Sarkaria, I., Singh, B., Heelan, R., Rusch, V., Fulton, L., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405220101 · Cited by 4,338 · see citing works
Pao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020073 · Cited by 3,527 · see citing works
High Frequency of Mutations of the PIK3CA Gene in Human Cancers
Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Gazdar, A. F., Powell, S. M., Riggins, G. J., et al. (2004) · Science · doi:10.1126/science.1096502 · Cited by 3,448 · see citing works
ERBB receptors and cancer: the complexity of targeted inhibitors
Hynes, N. E., & Lane, H. A. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1609 · Cited by 3,313 · see citing works
Oncogenic pathway signatures in human cancers as a guide to targeted therapies
Bild, A., Yao, G., Chang, J. T., Wang, Q., Potti, A., Chasse, D. A. D., Joshi, M.-B., Harpole, D. H., Lancaster, J. M., Berchuck, A., et al. (2005) · Nature · doi:10.1038/nature04296 · Cited by 2,032 · see citing works
Ras, PI(3)K and mTOR signalling controls tumour cell growth
Shaw, R. J., & Cantley, L. C. (2006) · Nature · doi:10.1038/nature04869 · Cited by 2,019 · see citing works
An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor
Zhang, X., Gureasko, J., Shen, K., Cole, P. A., & Kuriyan, J. (2006) · Cell · doi:10.1016/j.cell.2006.05.013 · Cited by 1,650 · see citing works
The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling
Lowenstein, E. J., Daly, R. J., Batzer, A., Li, W., Margolis, B. L., Lammers, R., Ullrich, A., Skolnik, E. Y., Bar‐Sagi, D., & Schlessinger, J. (1992) · Cell · doi:10.1016/0092-8674(92)90167-b · Cited by 1,632 · see citing works
Epidermal growth factor receptor: Mechanisms of activation and signalling
Jorissen, R. (2003) · Experimental Cell Research · doi:10.1016/s0014-4827(02)00098-8 · Cited by 1,565 · see citing works
Cappuzzo, F., Hirsch, F. R., Rossi, E., Bartolini, S., Ceresoli, G. L., Bemis, L., Haney, J., Witta, S. E., Danenberg, K. D., Domenichini, I., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji112 · Cited by 1,538 · see citing works
KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib
Pao, W. J., Wang, T. Y., Riely, G. J., Miller, V. A., Pan, Q., Ladanyi, M., Zakowski, M. F., Heelan, R. T., Kris, M. G., & VARMUS, H. E. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020017 · Cited by 1,517 · see citing works
BRAF mutation predicts sensitivity to MEK inhibition
Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G. A., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., et al. (2005) · Nature · doi:10.1038/nature04304 · Cited by 1,317 · see citing works
Transcriptional Regulation by Extracellular signals: Mechanisms and Specificity
Hill, C. S., & Treisman, R. (1995) · Cell · doi:10.1016/0092-8674(95)90403-4 · Cited by 1,263 · see citing works
Yeatman, T. J. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1366 · Cited by 1,113 · see citing works
Nuclear localization of EGF receptor and its potential new role as a transcription factor
Lin, S., Makino, K., Xia, W., Matin, A., Wen, Y., Kwong, K. Y., Bourguignon, L., & Hung, M. (2001) · Nature Cell Biology · doi:10.1038/ncb0901-802 · Cited by 1,064 · see citing works
Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR
Neshat, M. S., Mellinghoff, I. K., Tran, C., Stiles, B. L., THOMAS, G. V., Petersen, R., Frost, P., Gibbons, J. J., Wu, H., & Sawyers, C. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171076798 · Cited by 968 · see citing works
An Open-and-Shut Case? Recent Insights into the Activation of EGF/ErbB Receptors
Burgess, A. W., Cho, H., Eigenbrot, C. W., Ferguson, K. M., Garrett, T., Leahy, D. J., Lemmon, M. A., Sliwkowski, M. X., Ward, C. W., & Yokoyama, S. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00350-2 · Cited by 908 · see citing works
γ-Secretase Cleavage and Nuclear Localization of ErbB-4 Receptor Tyrosine Kinase
Ni, C.-Y., Murphy, M. P., Golde, T. E., & Carpenter, G. F. (2001) · Science · doi:10.1126/science.1065412 · Cited by 858 · see citing works
Bromberg, J. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15617 · Cited by 846 · see citing works
Intragenic ERBB2 kinase mutations in tumours
Stephens, P., Hunter, C., Bignell, G., Edkins, S., Davies, H., Teague, J., Stevens, C., O'Meara, S., Smith, R., Parker, A., et al. (2004) · Nature · doi:10.1038/431525b · Cited by 802 · see citing works
Schönwaßer, D. C., Marais, R., Marshall, C. J., & Parker, P. J. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.2.790 · Cited by 760 · see citing works
Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer
Baselga, J. M., & Arteaga, C. L. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.11.890 · Cited by 721 · see citing works
Self-citationDiversity and frequency of epidermal growth factor receptor mutations in human glioblastomas.
Frederick, L. A., Wang, X. Y., Eley, G. D., & James, C. D. (2000) · PubMed · Cited by 661 · see citing works
Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases
Carter, T. A., Wodicka, L. M., Shah, N. P., Velasco, A. M., Fabian, M. A., Treiber, D. K., Milanov, Z. V., Atteridge, C. E., Biggs, W., Edeen, P. T., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504952102 · Cited by 550 · see citing works
Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway
Lo, H., Hsu, S.-C., Ali‐Seyed, M., Gündüz, M., Xia, W., Wei, Y., Bartholomeusz, G. A., Shih, J. Y., & Hung, M. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.05.007 · Cited by 539 · see citing works
Hierarchy of Binding Sites for Grb2 and Shc on the Epidermal Growth Factor Receptor
Batzer, A., Rotin, D., Ureña, J. M., Skolnik, E. Y., & Schlessinger, J. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.8.5192 · Cited by 479 · see citing works
Politi, K., Zakowski, M. F., Fan, P.-D., Schonfeld, E. A., Pao, W., & Varmus, H. E. (2006) · Genes & Development · doi:10.1101/gad.1417406 · Cited by 478 · see citing works
Haura, E. B., Turkson, J., & Jove, R. (2005) · Nature Clinical Practice Oncology · doi:10.1038/ncponc0195 · Cited by 430 · see citing works
MAPKAP kinases — MKs — two's company, three's a crowd
Gaestel, M. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1834 · Cited by 413 · see citing works
EGFR signal transactivation in cancer cells
Fischer, O. M., Hart, S., Gschwind, A., & Ullrich, A. (2003) · Biochemical Society Transactions · doi:10.1042/bst0311203 · Cited by 412 · see citing works
Phase II and Tumor Pharmacodynamic Study of Gefitinib in Patients with Advanced Breast Cancer
Baselga, J. M., Albanell, J., Ruı́z, A., Lluch, A. M., Gascón, P., Guillém, V., González, S., Sauleda, S., Marimón, I., Tabernero, J. M., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.08.326 · Cited by 410 · see citing works
Self-citationLiu, D., Ghiso, J. A. A., Estrada, Y. D., & Ossowski, L. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00072-7 · Cited by 392 · see citing works
Carpenter, C. L., Auger, K. R., Chanudhuri, M., Yoakim, M., Schaffhausen, B. S., Shoelson, S. E., & Cantley, L. C. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)98375-4 · Cited by 388 · see citing works
Regulation of MAP kinase activity by peptide receptor signalling pathway: Paradigms of multiplicity
Liebmann, C. (2001) · Cellular Signalling · doi:10.1016/s0898-6568(01)00192-9 · Cited by 291 · see citing works
Novel Prognostic Value of Nuclear Epidermal Growth Factor Receptor in Breast Cancer
Lo, H., Xia, W., Wei, Y., Ali‐Seyed, M., Huang, S.-F. K., & Hung, M. (2005) · Cancer Research · doi:10.1158/0008-5472.338.65.1 · Cited by 287 · see citing works
Kobayashi, S., Ji, H., Yuza, Y., Meyerson, M., Wong, K.-K., Tenen, D. G., & Halmos, B. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1346 · Cited by 272 · see citing works
Endosomal Transport of ErbB-2: Mechanism for Nuclear Entry of the Cell Surface Receptor
Giri, D. K., Ali‐Seyed, M., Li, L., Lee, D., Ling, P., Bartholomeusz, G. A., Wang, S., & Hung, M. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.24.11005-11018.2005 · Cited by 242 · see citing works
Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation
Anido, J., Scaltriti, M., Bech Serra, J. J., Josefat, B. S., Rojo Todo, F., Baselga, J., & Arribas, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601191 · Cited by 231 · see citing works
Self-citationTreatment for Advanced Tumors: Src Reclaims Center Stage
Summy, J. M., & Gallick, G. E. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2692 · Cited by 224 · see citing works
Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation.
Hallberg, B., Rayter, S., & Downward, J. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)41718-2 · Cited by 223 · see citing works
Offterdinger, M., Schöfer, C., Weipoltshammer, K., & Grunt, T. W. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200109033 · Cited by 208 · see citing works
Mattoon, D., Lamothe, B., Lax, I., & Schlessinger, J. (2004) · BMC Biology · doi:10.1186/1741-7007-2-24 · Cited by 207 · see citing works
Co‐regulation of B‐Myb expression by E2F1 and EGF receptor
Hanada, N., Lo, H., Day, C., Pan, Y., Nakajima, Y., & Hung, M. (2005) · Molecular Carcinogenesis · doi:10.1002/mc.20147 · Cited by 188 · see citing works
Hierarchy of Binding Sites for Grb2 and Shc on the Epidermal Growth Factor Receptor
Batzer, A., Rotin, D., Ureña, J. M., et al. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.8.5192-5201.1994 · Cited by 170 · see citing works
Chattopadhyay, A., Vecchi, M., Ji, Q.-S., Mernaugh, R. L., & Carpenter, G. F. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.37.26091 · Cited by 146 · see citing works
Fujimoto, N., Wislez, M., Zhang, J., Iwanaga, K., Dackor, J., Hanna, A. E., Kalyankrishna, S., CODY, D. D., Price, R. E., Sato, M., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1977 · Cited by 146 · see citing works
Expression and Nuclear Localization of ErbB3 in Prostate Cancer
Koumakpayi, I. H., Diallo, J., Page, C. L., Lessard, L., Gleave, M. E., Bégin, L. R., Mes‐Masson, A., & Fred Saad, C. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-2242 · Cited by 140 · see citing works
Momentous sprint at the 2156 Olympics?
Tatem, A. J., Guerra, C. A., Atkinson, P. M., & Hay, S. I. (2004) · Nature · doi:10.1038/431525a · Cited by 140 · see citing works
Rojo, F., Tabernero, J., Albanell, J., Cutsem, E. V., Ohtsu, A., Doi, T., Koizumi, W., Shirao, K., Takiuchi, H., Cajal, S., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2005.04.2424 · Cited by 137 · see citing works
Self-citationPhospholipase C-γ: diverse roles in receptor-mediated calcium signaling
Patterson, R. L., van Rossum, D. B., Nikolaidis, N., Gill, D. L., & Snyder, S. H. (2005) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2005.10.005 · Cited by 121 · see citing works
Responsiveness to Cetuximab without Mutations inEGFR
Tsuchihashi, Z., Khambata‐Ford, S., Hanna, N. H., & Janne, P. A. (2005) · New England Journal of Medicine · doi:10.1056/nejm200507143530218 · Cited by 118 · see citing works
EGFR inhibitors: what have we learned from the treatment of lung cancer?
Giaccone, G., & Rodríguez, J. A. (2005) · Nature Clinical Practice Oncology · doi:10.1038/ncponc0341 · Cited by 83 · see citing works
Functional implication of the interaction between EGF receptor and C-SRC
Leu, T. (2003) · Frontiers in bioscience · doi:10.2741/980 · Cited by 77 · see citing works
McClellan, M. C., Kievit, P., Auersperg, N., et al. (1999) · Experimental Cell Research · doi:10.1006/excr.1998.4328 · Cited by 55 · see citing works
EGF receptor inhibition: Attacks on multiple fronts
Hubbard, S. R. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.04.004 · Cited by 47 · see citing works
Felip, E., Rojo, F., Reck, M., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.24.18_suppl.7160 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Richman, S. D., Seymour, M. T., Chambers, P., Elliott, F., Daly, C. L., Meade, A. M., Taylor, G., Barrett, J. H., & Quirke, P. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.22.4295 · Cited by 560 · see citing works
Molecular targeted therapy for anticancer treatment
Min, H.-Y., & Lee, H.-Y. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00864-3 · Cited by 569 · see citing works
Baldus, S. E., Schaefer, K.-L., Engers, R., Hartleb, D., Stoecklein, N. H., & Gabbert, H. E. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-2446 · Cited by 432 · see citing works
Zhang, N., Zeng, Y., Du, W., Zhu, J., Shen, D., Liu, Z., & Huang, J.-A. (2016) · International Journal of Oncology · doi:10.3892/ijo.2016.3632 · Cited by 362 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
Knijn, N., Mekenkamp, L. J. M., Klomp, M., Vink-Börger, M. E., Tol, J., Teerenstra, S., Meijer, J. W. R., Tebar, M., Riemersma, S., van Krieken, J. H. J. M., et al. (2011) · British Journal of Cancer · doi:10.1038/bjc.2011.26 · Cited by 291 · see citing works
EGFR family: Structure physiology signalling and therapeutic targets <sup>†</sup>
Burgess, A. W. (2008) · Growth Factors · doi:10.1080/08977190802312844 · Cited by 288 · see citing works
Ji, H., Wang, J., Nika, H., Hawke, D., Keezer, S., Ge, Q., Fang, B., Fang, X., Fang, D., Litchfield, D. W., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.034 · Cited by 270 · see citing works
Turley, E. A., Veiseh, M., Radisky, D. C., & Bissell, M. J. (2008) · Nature Clinical Practice Oncology · doi:10.1038/ncponc1089 · Cited by 253 · see citing works
HGF Rescues Colorectal Cancer Cells from EGFR Inhibition via MET Activation
Liska, D., Chen, C.-T., Bachleitner-Hofmann, T., Christensen, J. G., & Weiser, M. R. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-0568 · Cited by 176 · see citing works
Peyre, E., Silva, C. G., & Nguyen, L. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00129 · Cited by 51 · see citing works
Luca, T., Barresi, V., Privitera, G., Musso, N., Caruso, M., Condorelli, D. F., & Castorina, S. (2014) · Cell Proliferation · doi:10.1111/cpr.12125 · Cited by 27 · see citing works
Baba, Y., Tamura, T., Satoh, Y., Gotou, M., Sawada, H., Ebara, S., Shibuya, K., Soeda, J., & Nakamura, K. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12074 · Cited by 23 · see citing works
- Authors
- Scaltriti, M., & Baselga, J.
- Affiliations
- Universitat Autònoma de Barcelona (ES)
- Venue
- Clinical Cancer Research
- Published
- 2006-09-15
- Volume
- 12
- Issue
- 18
- Pages
- 5268-5272
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2161541244
- Cited by
- 913
- References
- 60
- Citations by year
- 2026: 21 · 2025: 31 · 2024: 38 · 2023: 42 · 2022: 46 · 2021: 49 · 2020: 50 · 2019: 60 · 2018: 50 · 2017: 51 · 2016: 58 · 2015: 48 · 2014: 68 · 2013: 41 · 2012: 43
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- epidermal growth factor receptor, EGFR, receptor tyrosine kinase, targeted cancer therapy, EGFR inhibitors, EGFR mutation, receptor activation, epithelial tumors, drug resistance
- MeSH terms
- Humans, Models, Biological, Mutation, Genes, ras, Signal Transduction, src-Family Kinases, Phosphatidylinositol 3-Kinases, Extracellular Signal-Regulated MAP Kinases, raf Kinases, STAT Transcription Factors, Oncogene Protein v-akt, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review