Kinetic Analysis of Epidermal Growth Factor Receptor Somatic Mutant Proteins Shows Increased Sensitivity to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib

Carey, Kendall D.; Garton, Andrew J.; Romero, Maria S.; Kahler, Jennifer; Thomson, Stuart; Ross, Sarajane; Park, Frances; Haley, John D.; Gibson, Neil; Sliwkowski, Mark X.

doi:10.1158/0008-5472.can-06-0453

Cited by 445HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsProtein Kinase Regulation and GTPase Signaling

Kinetic Analysis of Epidermal Growth Factor Receptor Somatic Mutant Proteins Shows Increased Sensitivity to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib

Carey, Kendall D., Garton, Andrew J., Romero, Maria S., Kahler, Jennifer, Thomson, Stuart, Ross, Sarajane, Park, Frances, Haley, John D. +2 more·2006·Cancer Research

DOI 10.1158/0008-5472.can-06-0453

Open this paper in CoChat — free account

Abstract

We show that two commonly occurring epidermal growth factor receptor (EGFR) somatic mutations, L858R and an in-frame deletion mutant, Del(746-750), exhibit distinct enzymatic properties relative to wild-type EGFR and are differentially sensitive to erlotinib. Kinetic analysis of the purified intracellular domains of EGFR L858R and EGFR Del(746-750) reveals that both mutants are active but exhibit a higher KM for ATP and a lower Ki for erlotinib relative to wild-type receptor. When expressed in NR6 cells, a cell line that does not express EGFR or other ErbB receptors, both mutations are ligand dependent for receptor activation, can activate downstream EGFR signaling pathways, and promote cell cycle progression. As expected from the kinetic analysis, the EGFR Del(746-752) is more sensitive to erlotinib inhibition than the EGFR L858R mutant. Further characterization shows that these mutations promote ligand-dependent and anchorage-independent growth, and cells harboring these mutant receptors form tumors in immunocompromised mice. Analysis of tumor lysates reveals that the tumorigenicity of the mutant EGFR cell lines may be due to a differential pattern of mutant EGFR autophosphorylation as compared with wild-type receptor. Significant inhibition of tumor growth, in mice harboring wild-type EGFR receptors, is only observed at doses of erlotinib approaching the maximum tolerated dose for the mouse. In contrast, the growth of mutant tumors is inhibited by erlotinib treatment at approximately one third the maximum tolerated dose. These findings suggest that EGFR somatic mutations directly influence both erlotinib sensitivity and cellular transformation. (Cancer Res 2006; 66(16): 8163-71)

Integrity signals

Registry

Crossref · 10.1158/0008-5472.can-06-0453

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

The sensitivity of EGFR-L858R and exon 19 deletions to TKIs stems from enhanced intrinsic affinity for TKIs and markedly decreased affinity for ATP.
“The exquisite sensitivity of EGFR-L858R and exon 19 deletions to EGFR TKIs stems from two effects: their enhanced intrinsic affinity for these TKIs and their markedly decreased affinity for substrate ATP 38,39.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [39]
The enhanced sensitivity of L858R and exon 19 deletion mutants relative to WT EGFR creates the therapeutic window that makes gefitinib and erlotinib useful drugs.
“Because the dose-limiting toxicities of gefitinib and erlotinib arise from inhibition of WT EGFR in normal tissues, the enhanced sensitivity of these mutants relative to WT EGFR effectively creates the “therapeutic window” that makes gefitinib and erlotinib useful drugs 39,50,56.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [39]
The similar ATP and TKI binding properties of D770_N771insNPG compared with WT EGFR suggest that it will be difficult to achieve the requisite selectivity versus WT receptor.
“Additionally, the similar ATP and TKI binding properties of this mutant, as compared with WT EGFR, suggest that it will be difficult to achieve the requisite selectivity versus the WT receptor 39,50,56,58,59.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [39]
The dose-limiting toxicities of gefitinib and erlotinib arise from inhibition of WT EGFR in normal tissues.
“Because the dose-limiting toxicities of gefitinib and erlotinib arise from inhibition of WT EGFR in normal tissues, the enhanced sensitivity of these mutants relative to WT EGFR effectively creates the “therapeutic window” that makes gefitinib and erlotinib useful drugs 39,50,56.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [39]

Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib
Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Haserlat, S. M., Supko, J. G., Haluska, F. G., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040938 · Cited by 11,486 · see citing works
EGFR 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
Erlotinib in Previously Treated Non–Small-Cell Lung Cancer
Shepherd, F. A., Rodrigues Pereira, J., Ciuleanu, T., Tan, E. H., Hirsh, V., Thongprasert, S., Campos, D., Maoleekoonpiroj, S., Smylie, M., Martins, R., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050753 · Cited by 5,419 · see citing works
EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib
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
Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers
Shigematsu, H., Lin, L., Takahashi, T., Nomura, M., Suzuki, M., Wistuba, I. I., Fong, K. M., Lee, H., Toyooka, S., Shimizu, N., et al. (2005) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/dji055 · Cited by 2,377 · see citing works
Erlotinib in Lung Cancer — Molecular and Clinical Predictors of Outcome
Tsao, M., Sakurada, A., Cutz, J.-C., Zhu, C., Kamel‐Reid, S., Squire, J. A., Lorimer, I. A. J., Zhang, T., Liu, G., Daneshmand, M., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050736 · Cited by 1,815 · see citing works
Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways
Sordella, R., Bell, D. W., Haber, D. A., & Settleman, J. E. (2004) · Science · doi:10.1126/science.1101637 · Cited by 1,605 · see citing works
Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor
Stamos, J. L., Sliwkowski, M. X., & Eigenbrot, C. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m207135200 · Cited by 1,594 · see citing works
Self-citation
TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer
Herbst, R. S., Prager, D., Hermann, R., Fehrenbacher, L., Johnson, B. E., Sandler, A., Kris, M. G., Tran, H. T., Klein, P., Li, X., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.02.840 · Cited by 1,490 · see citing works
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
Eberhard, D. A., Johnson, B. E., Amler, L. C., Goddard, A. D., Heldens, S., Herbst, R. S., Ince, W. L., Janne, P. A., Januario, T., Johnson, D. H., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.02.857 · Cited by 1,453 · see citing works
The EGF receptor family as targets for cancer therapy
Mendelsohn, J. M., & Baselga, J. M. (2000) · Oncogene · doi:10.1038/sj.onc.1204082 · Cited by 1,341 · see citing works
A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib)
Wood, E. R., Truesdale, A. T., McDonald, O. B., Yuan, D. Y., Hassell, A. M., Dickerson, S. H., Ellis, B., Pennisi, C., Horne, E., Lackey, K. E., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1168 · Cited by 1,130 · see citing works
Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib
Kwak, E. L., Sordella, R., Bell, D. W., Godin-Heymann, N., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Driscoll, D. R., Fidias, P. M., Lynch, T. J., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502860102 · Cited by 950 · see citing works
Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase.
Moyer, J. D., Barbacci, E. G., Iwata, K. K., Arnold, L., Boman, B., Cunningham, A., DiOrio, C., Doty, J., Morin, M. J., Moyer, M. P., et al. (1997) · PubMed · doi:10.7270/q2dr317m · Cited by 841 · see citing works
Predictive and Prognostic Impact of Epidermal Growth Factor Receptor Mutation in Non–Small-Cell Lung Cancer Patients Treated With Gefitinib
Han, S., Kim, T., Hwang, P. G., Jeong, S., Kim, J., Choi, I. S., Oh, D., Kim, J. H., Kim, D., Chung, D. H., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.01.388 · Cited by 757 · see citing works
Epidermal Growth Factor Receptor Gene Mutations and Increased Copy Numbers Predict Gefitinib Sensitivity in Patients With Recurrent Non–Small-Cell Lung Cancer
Takano, T., Ohe, Y., Sakamoto, H., Tsuta, K., Matsuno, Y., Tateishi, U., Yamamoto, S., Nokihara, H., Yamamoto, N., Sekine, I., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.01.0793 · Cited by 691 · see citing works
A Grb2-associated docking protein in EGF- and insulin-receptor signalling
Holgado-Madruga, M., Emlet, D. R., Moscatello, D. K., Godwin, A. K., & Wong, A. J. (1996) · Nature · doi:10.1038/379560a0 · Cited by 677 · see citing works
Epithelial to Mesenchymal Transition Is a Determinant of Sensitivity of Non–Small-Cell Lung Carcinoma Cell Lines and Xenografts to Epidermal Growth Factor Receptor Inhibition
Thomson, S., Buck, E. A., Petti, F., Griffin, G., Brown, E., Ramnarine, N., Iwata, K. K., Gibson, N. W., & Haley, J. D. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1058 · Cited by 663 · see citing works
Self-citation
Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells
Fiore, P. P. D., Pierce, J. H., Fleming, T. P., Hazan, R., Ullrich, A., King, C. R., Schlessinger, J., & Aaronson, S. A. (1987) · Cell · doi:10.1016/0092-8674(87)90592-7 · Cited by 641 · see citing works
Epidermal Growth Factor Receptor Mutations, Small-Molecule Kinase Inhibitors, and Non–Small-Cell Lung Cancer: Current Knowledge and Future Directions
Pao, W. J., & Miller, V. A. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.07.799 · Cited by 628 · see citing works
High Frequency of Epidermal Growth Factor Receptor Mutations with Complex Patterns in Non–Small Cell Lung Cancers Related to Gefitinib Responsiveness in Taiwan
Huang, S.-F. K., Liu, H.-P., Li, L.-H., Ku, Y.-C., Fu, Y.-N., Tsai, H., Chen, Y.-T., Lin, Y., Chang, W.-C., Kuo, H.-P., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1245 · Cited by 545 · see citing works
Epithelial versus Mesenchymal Phenotype Determines In vitro Sensitivity and Predicts Clinical Activity of Erlotinib in Lung Cancer Patients
Yauch, R. L., Januario, T., Eberhard, D. A., Cavet, G., Zhu, W., Fu, L., Pham, T. Q., Soriano, R., Stinson, J., Seshagiri, S., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1492 · Cited by 495 · see citing works
ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines
Engelman, J. A., Janne, P. A., Mermel, C. H., Pearlberg, J., Mukohara, T., Fleet, C., Cichowski, K. M., Johnson, B. E., & Cantley, L. C. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409773102 · Cited by 494 · 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
Inhibition of Epidermal Growth Factor Receptor-Associated Tyrosine Phosphorylation in Human Carcinomas with CP-358,774: Dynamics of Receptor Inhibition In Situ and Antitumor Effects in Athymic Mice
Pollack, V. A., Savage, D. M., Baker, D. A., Tsaparikos, K. E., Sloan, D. E., Moyer, J. D., Barbacci-Tobin, E. G., Pustilnik, L. R., Smolarek, T. A., Davis, J. A., et al. (1999) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)35162-6 · Cited by 435 · see citing works
Epidermal-Growth-Factor-Dependent Transformation by a Human EGF Receptor Proto-Oncogene
Velu, T. J., Beguinot, L., Vass, W. C., Willingham, M. C., Merlino, G. T., Pastan, I. H., & Lowy, D. R. (1987) · Science · doi:10.1126/science.3500513 · Cited by 433 · see citing works
Aberrant Epidermal Growth Factor Receptor Signaling and Enhanced Sensitivity to EGFR Inhibitors in Lung Cancer
Amann, J. M., Kalyankrishna, S., Massion, P. P., Ohm, J. E., Girard, L., Shigematsu, H., Peyton, M., Juroske, D. M., Huang, Y., Salmon, J. S., et al. (2005) · Cancer Research · doi:10.1158/0008-5472.226.65.1 · Cited by 432 · see citing works
Mutation in the Tyrosine Kinase Domain of Epidermal Growth Factor Receptor Is a Predictive and Prognostic Factor for Gefitinib Treatment in Patients with Non–Small Cell Lung Cancer
Chou, T., Chiu, C., Li, L., Hsiao, C.-Y., Tzen, C., Chang, K.-T., Chen, Y., Perng, R.-P., Tsai, S., & Tsai, C. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1981 · Cited by 315 · see citing works
Mutations and addiction to EGFR: the Achilles ‘heal’ of lung cancers?
Gazdar, A. F., Shigematsu, H., Herz, J., & Minna, J. D. (2004) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2004.08.008 · Cited by 293 · see citing works
Approval Summary for Erlotinib for Treatment of Patients with Locally Advanced or Metastatic Non–Small Cell Lung Cancer after Failure of at Least One Prior Chemotherapy Regimen
Johnson, J. R., Cohen, M. H., Sridhara, R., Chen, Y., Williams, G. M., Duan, J. Z., Gobburu, J. V. S., Booth, B. P., Benson, K. A., Leighton, J., et al. (2005) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-0790 · Cited by 224 · see citing works
Epidermal Growth Factor–Independent Transformation of Ba/F3 Cells with Cancer-Derived Epidermal Growth Factor Receptor Mutants Induces Gefitinib-Sensitive Cell Cycle Progression
Jiang, J., Greulich, H. E., Janne, P. A., Sellers, W. R., Meyerson, M. M., & Griffin, J. D. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1829 · Cited by 188 · see citing works
Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation
Grøvdal, L. M., Stang, E., Sorkin, A. D., & Madshus, I. H. (2004) · Experimental Cell Research · doi:10.1016/j.yexcr.2004.07.003 · Cited by 182 · see citing works
Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839)
Kakiuchi, S., Daigo, Y., Ishikawa, N., Furukawa, C., Tsunoda, T., Yano, S., Nakagawa, K., Tsuruo, T., Kohno, N., Fukuoka, M., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh331 · Cited by 173 · see citing works
Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor.
Chazin, V. R., Kaleko, M., Miller, A. D., et al. (1992) · PubMed · Cited by 173 · 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
Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models
Higgins, B., Kolinsky, K. D., Smith, M. L., Beck, G., Rashed, M., Adames, V., Linn, M., Wheeldon, E. B., Gand, L., Birnboeck, H., et al. (2004) · Anti-Cancer Drugs · doi:10.1097/01.cad.0000127664.66472.60 · Cited by 152 · see citing works
Epidermal Growth Factor Receptor Mutations in Patients with Non–Small Cell Lung Cancer
Johnson, B. E., & Janne, P. A. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1257 · Cited by 147 · see citing works
Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients.
Malik, S. N., Siu, L. L., Rowinsky, E. K., et al. (2003) · PubMed · Cited by 130 · see citing works
Tyrosines 1148 and 1173 of activated human epidermal growth factor receptors are binding sites of Shc in intact cells
Okabayashi, Y., Kido, Y., Okutani, T., Sugimoto, Y., Sakaguchi, K., & Kasuga, M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32363-3 · Cited by 118 · see citing works
HER2 Overexpression Increases Sensitivity to Gefitinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, through Inhibition of HER2/HER3 Heterodimer Formation in Lung Cancer Cells
Hirata, A., Hosoi, F., Miyagawa, M., Ueda, S.-I., Naito, S., Fujii, T., Kuwano, M., & Ono, M. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-2748 · Cited by 109 · see citing works
Pharmacokinetics and pharmacodynamics: Maximizing the clinical potential of Erlotinib (Tarceva)
Hidalgo, M. M., & Bloedow, D. C. (2003) · Seminars in Oncology · doi:10.1016/s0093-7754(03)70012-8 · Cited by 99 · see citing works
The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer
Zhang, X.-T., Li, L.-Y., Mu, X. L., Cui, Q.-C., Chang, X.-Y., Song, W., Wang, S., Wang, M., Zhong, W., & Zhang, L. (2005) · Annals of Oncology · doi:10.1093/annonc/mdi340 · Cited by 96 · see citing works
Skin rash and good performance status predict improved survival with gefitinib in patients with advanced non-small cell lung cancer
Mohamed, M. K., Ramalingam, S. S., Lin, Y., et al. (2005) · Annals of Oncology · doi:10.1093/annonc/mdi157 · Cited by 93 · see citing works
c-Cbl-mediated Ubiquitinylation Is Required for Epidermal Growth Factor Receptor Exit from the Early Endosomes
Ravid, T., Heidinger, J. M., Gee, P., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403210200 · Cited by 89 · see citing works
Structure, function and transforming potential of the epidermal growth factor receptor
Velu, T. J. (1990) · Molecular and Cellular Endocrinology · doi:10.1016/0303-7207(90)90211-p · Cited by 64 · see citing works
Antibody-mediated EGF receptor blockade as an anticancer therapy: from the laboratory to the clinic
Mendelsohn, J. M. (2003) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-002-0354-7 · Cited by 58 · see citing works
Analysis of mammalian fibroblast transformation by normal and mutated human EGF receptors.
Jd, H., Hsuan, J. J., & Waterfield, M. D. (1989) · PubMed · Cited by 53 · see citing works
3T3 variants lacking receptors for epidermal growth factor are susceptible to transformation by Kirsten sarcoma virus
Pruss, R. M., Herschman, H. R., & Klement, V. (1978) · Nature · doi:10.1038/274272a0 · Cited by 19 · see citing works
Abelson transformed fibroblasts lacking the EGF receptor are not tumourigenic in nude mice.
Gebhardt, A., Bell, J. C., & Foulkes, J. G. (1986) · The EMBO Journal · doi:10.1002/j.1460-2075.1986.tb04483.x · Cited by 15 · see citing works
Antitumor Activity and Tolerability of Gefitinib in Patients with Non–Small-Cell Lung Cancer Treated in an Expanded Access Program
Shah, N. T., & Miller, V. A. (2003) · Clinical Lung Cancer · doi:10.3816/clc.2003.n.032 · Cited by 5 · see citing works

Flagged first, then by citations

Sorted by citations

Epidermal growth factor receptor mutations in lung cancer
Sharma, S. V., Bell, D. W., Settleman, J., & Haber, D. A. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2088 · Cited by 3,170 · see citing works
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Yun, C.-H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K.-K., Meyerson, M., & Eck, M. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709662105 · Cited by 2,118 · see citing works
Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity
Yun, C.-H., Boggon, T. J., Li, Y., Woo, M. S., Greulich, H., Meyerson, M., & Eck, M. J. (2007) · Cancer Cell · doi:10.1016/j.ccr.2006.12.017 · Cited by 1,192 · see citing works
Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer
Pao, W., & Chmielecki, J. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2947 · Cited by 1,083 · see citing works
ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics
Arteaga, C. L., & Engelman, J. A. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.025 · Cited by 1,048 · see citing works
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., et al. (2009) · Nature · doi:10.1038/nature08622 · Cited by 1,013 · see citing works
Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors
Gazdar, A. F. (2009) · Oncogene · doi:10.1038/onc.2009.198 · Cited by 991 · see citing works
PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models with EGFR and ERBB2 Mutations that Are Resistant to Gefitinib
Engelman, J. A., Zejnullahu, K., Gale, C.-M., Lifshits, E., Gonzales, A. J., Shimamura, T., Zhao, F., Vincent, P. W., Naumov, G. N., Bradner, J. E., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1885 · Cited by 730 · see citing works
Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer
Mitsudomi, T., & Yatabe, Y. (2007) · Cancer Science · doi:10.1111/j.1349-7006.2007.00607.x · Cited by 606 · see citing works
Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer
Yasuda, H., Park, E., Yun, C.-H., Sng, N. J., Lucena-Araujo, A. R., Yeo, W.-L., Huberman, M. S., Cohen, D. W., Nakayama, S., Ishioka, K., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3007205 · Cited by 571 · see citing works
Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data
Chen, W. W., Schoeberl, B., Jasper, P. J., Niepel, M., Nielsen, U. B., Lauffenburger, D. A., & Sorger, P. K. (2009) · Molecular Systems Biology · doi:10.1038/msb.2008.74 · Cited by 391 · see citing works
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations
Chiu, C.-H., Yang, C.-T., Shih, J.-Y., Huang, M.-S., Su, W.-C., Lai, R.-S., Wang, C.-C., Hsiao, S.-H., Lin, Y.-C., Ho, C.-L., et al. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000504 · Cited by 241 · see citing works
Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC
Riess, J. W., Gandara, D. R., Frampton, G. M., Madison, R., Peled, N., Bufill, J. A., Dy, G. K., Ou, S.-H. I., Stephens, P. J., McPherson, J. D., et al. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.06.019 · Cited by 240 · see citing works
Correlation between mouse age and human age in anti-tumor research: Significance and method establishment
Wang, S., Lai, X., Deng, Y., & Song, Y. (2020) · Life Sciences · doi:10.1016/j.lfs.2019.117242 · Cited by 228 · see citing works
Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer
Eck, M. J., & Yun, C.-H. (2010) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2009.12.010 · Cited by 225 · see citing works
EGFR-mutated lung cancer: a paradigm of molecular oncology
Zhang, Z., Stiegler, A. L., Boggon, T. J., Kobayashi, S., & Halmos, B. (2010) · Oncotarget · doi:10.18632/oncotarget.186 · Cited by 197 · see citing works
Epidermal Growth Factor Receptor Mutants from Human Lung Cancers Exhibit Enhanced Catalytic Activity and Increased Sensitivity to Gefitinib
Mulloy, R., Ferrand, A., Kim, Y., Sordella, R., Bell, D. W., Haber, D. A., Anderson, K. S., & Settleman, J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4293 · Cited by 192 · see citing works
Patients with Exon 19 Deletion Were Associated with Longer Progression-Free Survival Compared to Those with L858R Mutation after First-Line EGFR-TKIs for Advanced Non-Small Cell Lung Cancer: A Meta-Analysis
Zhang, Y., Sheng, J., Kang, S., Fang, W., Yan, Y., Hu, Z., Hong, S., Wu, X., Qin, T., Liang, W., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107161 · Cited by 175 · see citing works
EGFR Exon 19 Insertions: A New Family of Sensitizing EGFR Mutations in Lung Adenocarcinoma
He, M., Capelletti, M., Nafa, K., Yun, C.-H., Arcila, M. E., Miller, V. A., Ginsberg, M. S., Zhao, B., Kris, M. G., Eck, M. J., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2361 · Cited by 149 · see citing works
Antitumor activity of targeted and cytotoxic agents in murine subcutaneous tumor models correlates with clinical response
Wong, H., Choo, E. F., Alicke, B., Ding, X., La, H., McNamara, E., Theil, F.-P., Tibbitts, J., Friedman, L. S., Hop, C. E. C. A., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0738 · Cited by 133 · see citing works
Uncommon Epidermal Growth Factor Receptor mutations in non-small cell lung cancer and their mechanisms of EGFR tyrosine kinase inhibitors sensitivity and resistance
Massarelli, E., Johnson, F. M., Erickson, H. S., Wistuba, I. I., & Papadimitrakopoulou, V. (2013) · Lung Cancer · doi:10.1016/j.lungcan.2013.01.018 · Cited by 110 · see citing works
Common EGFR -Mutated Subgroups (Del19/L858R) in Advanced Non-Small-Cell Lung Cancer: Chasing Better Outcomes with Tyrosine Kinase Inhibitors
Reguart, N., & Remon, J. (2015) · Future Oncology · doi:10.2217/fon.15.15 · Cited by 91 · see citing works
Noncovalent Wild-type–Sparing Inhibitors of EGFR T790M
Lee, H.-J., Schaefer, G., Heffron, T. P., Shao, L., Ye, X., Sideris, S., Malek, S., Chan, E., Merchant, M., La, H., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0357 · Cited by 90 · see citing works
Mitochondrial Ubiquitin Ligase MARCH5 Promotes TLR7 Signaling by Attenuating TANK Action
Shi, H.-X., Liu, X., Wang, Q., Tang, P.-P., Liu, X.-Y., Shan, Y.-F., & Wang, C. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002057 · Cited by 67 · see citing works

Comparison of the therapeutic outcome between gefitinib and erlotinib in female patients with non-small-cell lung cancer
문대성, 장태원, Ok, C. H., 정만홍, 김도현, & 최인수 (2009) · The Korean Journal of Internal Medicine
Gefitinib or erlotinib in the treatment of advanced non-small cell lung cancer.
Shao, Y., Lin, C., & Yang, C.-H. (2010) · PubMed · Cited by 13 · see citing works
Successful Treatment of Non-small Cell Lung Cancer with Gefitinib after Severe Erlotinib-related Hepatotoxicity
Kunimasa, K., Yoshioka, H., Iwasaku, M., et al. (2012) · Internal Medicine · doi:10.2169/internalmedicine.51.6285 · Cited by 26 · see citing works
Erlotinib as a salvage treatment for patients with advanced non-small cell lung cancer after failure of gefitinib treatment
Сонг, Zheng-bo, Yu, et al. (2011) · 中华医学杂志：英文版
Erlotinib is a well-tolerated alternate treatment for non-small cell lung cancer in cases of gefitinib-induced hepatotoxicity.
Yonesaka, K., Suzumura, T., Tsukuda, H., Hasegawa, Y., Ozaki, T., Sugiura, T., & Fukuoka, M. (2014) · PubMed · Cited by 13 · see citing works

Authors: Carey, K. D., Garton, A. J., Romero, M. S., Kahler, J., Thomson, S., Ross, S., Park, F., Haley, J. D., Gibson, N., & Sliwkowski, M. X.
Affiliations: Genentech (US)
2Translational Research, OSI Pharmaceuticals, Farmingdale, New York; and
3SGX Pharmaceuticals, Inc., San Diego, California
ORCID: Kahler, Jennifer
Thomson, Stuart
Haley, John D.
Sliwkowski, Mark X.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2006-08-15
Volume: 66
Issue: 16
Pages: 8163-8171
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-06-0453
OpenAlex: W2145497412
Cited by: 445
References: 50
Citations by year: 2026: 6 · 2025: 14 · 2024: 14 · 2023: 24 · 2022: 24 · 2021: 25 · 2020: 24 · 2019: 18 · 2018: 26 · 2017: 27 · 2016: 27 · 2015: 28 · 2014: 26 · 2013: 31 · 2012: 25
FWCI: 9.74
Type: journal article
Language: en
Open access: closed
Locations: 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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: epidermal growth factor receptor, L858R mutation, in-frame deletion mutants, erlotinib, tyrosine kinase inhibitor sensitivity, receptor tyrosine kinase, ATP affinity, ligand-dependent receptor activation, autophosphorylation, anchorage-independent growth, tumor growth inhibition, cell transformation, EGFR signaling
MeSH terms: Erlotinib Hydrochloride, Cell Division, Cell Transformation, Neoplastic, Cloning, Molecular, Genetic Vectors, Humans, Kinetics, Mutation, Quinazolines, Mutagenesis, Sequence Deletion, Cell Line, Tumor, Protein Kinase Inhibitors, 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

Kinetic Analysis of Epidermal Growth Factor Receptor Somatic Mutant Proteins Shows Increased Sensitivity to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Related

Record

About these checks