Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib
Thomas J. Lynch, M.D., Daphne W. Bell, Ph.D., Raffaella Sordella, Ph.D., Sarada Gurubhagavatula, M.D., Ross A. Okimoto, B.S., Brian W. Brannigan, B.A., Patricia L. Harris, M.S., Sara M. Haserlat, B.A., Jeffrey G. Supko, Ph.D., Frank G. Haluska, M.D., Ph.D., David N. Louis, M.D., David C. Christiani, M.D., Jeff Settleman, Ph.D., and Daniel A. Haber, M.D., Ph.D.
Background Most patients with non–small-cell lung cancerhave no response to the tyrosine kinase inhibitor gefitinib,which targets the epidermal growth factor receptor (EGFR). However,about 10 percent of patients have a rapid and often dramaticclinical response. The molecular mechanisms underlying sensitivityto gefitinib are unknown.
Methods We searched for mutations in the EGFR gene in primarytumors from patients with non–small-cell lung cancer whohad a response to gefitinib, those who did not have a response,and those who had not been exposed to gefitinib. The functionalconsequences of identified mutations were evaluated after themutant proteins were expressed in cultured cells.
Results Somatic mutations were identified in the tyrosine kinasedomain of the EGFR gene in eight of nine patients with gefitinib-responsivelung cancer, as compared with none of the seven patients withno response (P<0.001). Mutations were either small, in-framedeletions or amino acid substitutions clustered around the ATP-bindingpocket of the tyrosine kinase domain. Similar mutations weredetected in tumors from 2 of 25 patients with primary non–small-celllung cancer who had not been exposed to gefitinib (8 percent).All mutations were heterozygous, and identical mutations wereobserved in multiple patients, suggesting an additive specificgain of function. In vitro, EGFR mutants demonstrated enhancedtyrosine kinase activity in response to epidermal growth factorand increased sensitivity to inhibition by gefitinib.
Conclusions A subgroup of patients with non–small-celllung cancer have specific mutations in the EGFR gene, whichcorrelate with clinical responsiveness to the tyrosine kinaseinhibitor gefitinib. These mutations lead to increased growthfactor signaling and confer susceptibility to the inhibitor.Screening for such mutations in lung cancers may identify patientswho will have a response to gefitinib.
Source Information
From the Cancer Center (T.J.L., D.W.B., R.S., S.G., R.A.O., B.W.B., P.L.H., S.M.H., J.G.S., F.G.H., D.N.L., D.C.C., J.S., D.A.H.) and the Departments of Medicine (T.J.L., D.W.B., J.G.S., F.G.H., D.C.C., J.S., D.A.H.) and Pathology (D.N.L.), Massachusetts General Hospital and Harvard Medical School; and the Harvard School of Public Health (S.G., D.C.C.) — all in Boston. Drs. Lynch, Bell, and Sordella contributed equally to the article. This article was published at www.nejm.org on April 29, 2004.
Address reprint requests to Dr. Haber at MGH Cancer Center, Bldg. 149, 13th St., Charlestown, MA 02129, or at haber{at}helix.mgh.harvard.edu.
Ling, Y.-H., Lin, R., Perez-Soler, R.
(2008). Erlotinib Induces Mitochondrial-Mediated Apoptosis in Human H3255 Non-Small-Cell Lung Cancer Cells with Epidermal Growth Factor ReceptorL858R Mutation through Mitochondrial Oxidative Phosphorylation-Dependent Activation of BAX and BAK. Mol. Pharmacol.
74: 793-806
[Abstract][Full Text]
Zannetti, A., Iommelli, F., Fonti, R., Papaccioli, A., Sommella, J., Lettieri, A., Pirozzi, G., Bianco, R., Tortora, G., Salvatore, M., Del Vecchio, S.
(2008). Gefitinib Induction of In vivo Detectable Signals by Bcl-2/Bcl-xL Modulation of Inositol Trisphosphate Receptor Type 3. Clin. Cancer Res.
14: 5209-5219
[Abstract][Full Text]
Azad, N. S., Posadas, E. M., Kwitkowski, V. E., Steinberg, S. M., Jain, L., Annunziata, C. M., Minasian, L., Sarosy, G., Kotz, H. L., Premkumar, A., Cao, L., McNally, D., Chow, C., Chen, H. X., Wright, J. J., Kohn, E. C.
(2008). Combination Targeted Therapy With Sorafenib and Bevacizumab Results in Enhanced Toxicity and Antitumor Activity. JCO
26: 3709-3714
[Abstract][Full Text]
Seo, H.-S., Liu, D. D., Bekele, B. N., Kim, M.-K., Pisters, K., Lippman, S. M., Wistuba, I. I., Koo, J. S.
(2008). Cyclic AMP Response Element-Binding Protein Overexpression: A Feature Associated with Negative Prognosis in Never Smokers with Non-Small Cell Lung Cancer. Cancer Res.
68: 6065-6073
[Abstract][Full Text]
Tang, X., Varella-Garcia, M., Xavier, A. C., Massarelli, E., Ozburn, N., Moran, C., Wistuba, I. I.
(2008). Epidermal Growth Factor Receptor Abnormalities in the Pathogenesis and Progression of Lung Adenocarcinomas. Cancer Prevention Research
1: 192-200
[Abstract][Full Text]
Fukui, T., Ohe, Y., Tsuta, K., Furuta, K., Sakamoto, H., Takano, T., Nokihara, H., Yamamoto, N., Sekine, I., Kunitoh, H., Asamura, H., Tsuchida, T., Kaneko, M., Kusumoto, M., Yamamoto, S., Yoshida, T., Tamura, T.
(2008). Prospective Study of the Accuracy of EGFR Mutational Analysis by High-Resolution Melting Analysis in Small Samples Obtained from Patients with Non-Small Cell Lung Cancer. Clin. Cancer Res.
14: 4751-4757
[Abstract][Full Text]
Wu, J.-Y., Wu, S.-G., Yang, C.-H., Gow, C.-H., Chang, Y.-L., Yu, C.-J., Shih, J.-Y., Yang, P.-C.
(2008). Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Mutations Is Associated with Poor Gefitinib Treatment Response. Clin. Cancer Res.
14: 4877-4882
[Abstract][Full Text]
Pino, M. S., Balsamo, M., Di Modugno, F., Mottolese, M., Alessio, M., Melucci, E., Milella, M., McConkey, D. J., Philippar, U., Gertler, F. B., Natali, P. G., Nistico, P.
(2008). Human Mena+11a Isoform Serves as a Marker of Epithelial Phenotype and Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Pancreatic Cancer Cell Lines. Clin. Cancer Res.
14: 4943-4950
[Abstract][Full Text]
Zhang, J., Iwanaga, K., Choi, K. C., Wislez, M., Raso, M. G., Wei, W., Wistuba, I. I., Kurie, J. M.
(2008). Intratumoral Epiregulin Is a Marker of Advanced Disease in Non-Small Cell Lung Cancer Patients and Confers Invasive Properties on EGFR-Mutant Cells. Cancer Prevention Research
1: 201-207
[Abstract][Full Text]
Sequist, L. V., Settleman, J. E., Ackman, J. B., Iafrate, A. J.
(2008). Case 23-2008 -- A 26-Year-Old Man with Back Pain and a Mass in the Lung. NEJM
359: 405-414
[Full Text]
Schiller, J. H.
(2008). Noninvasive Monitoring of Tumors. NEJM
359: 418-420
[Full Text]
Maheswaran, S., Sequist, L. V., Nagrath, S., Ulkus, L., Brannigan, B., Collura, C. V., Inserra, E., Diederichs, S., Iafrate, A. J., Bell, D. W., Digumarthy, S., Muzikansky, A., Irimia, D., Settleman, J., Tompkins, R. G., Lynch, T. J., Toner, M., Haber, D. A.
(2008). Detection of Mutations in EGFR in Circulating Lung-Cancer Cells. NEJM
359: 366-377
[Abstract][Full Text]
Villalona-Calero, M. A., Otterson, G. A., Wientjes, M. G., Weber, F., Bekaii-Saab, T., Young, D., Murgo, A. J., Jensen, R., Yeh, T.-K., Wei, Y., Zhang, Y., Eng, C., Grever, M., Au, J. L.-S.
(2008). Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study. Ann Oncol
0: mdn412v1-mdn412
[Abstract][Full Text]
Braiteh, F., Kurzrock, R., Johnson, F. M.
(2008). Trichomegaly of the Eyelashes After Lung Cancer Treatment with the Epidermal Growth Factor Receptor Inhibitor Erlotinib. JCO
26: 3460-3462
[Full Text]
Choi, Y. L., Takeuchi, K., Soda, M., Inamura, K., Togashi, Y., Hatano, S., Enomoto, M., Hamada, T., Haruta, H., Watanabe, H., Kurashina, K., Hatanaka, H., Ueno, T., Takada, S., Yamashita, Y., Sugiyama, Y., Ishikawa, Y., Mano, H.
(2008). Identification of Novel Isoforms of the EML4-ALK Transforming Gene in Non-Small Cell Lung Cancer. Cancer Res.
68: 4971-4976
[Abstract][Full Text]
Ko, J.-C., Ciou, S.-C., Cheng, C.-M., Wang, L.-H., Hong, J.-H., Jheng, M.-Y., Ling, S.-T., Lin, Y.-W.
(2008). Involvement of Rad51 in cytotoxicity induced by epidermal growth factor receptor inhibitor (gefitinib, IressaR) and chemotherapeutic agents in human lung cancer cells. Carcinogenesis
29: 1448-1458
[Abstract][Full Text]
Bell, D. W., Brannigan, B. W., Matsuo, K., Finkelstein, D. M., Sordella, R., Settleman, J., Mitsudomi, T., Haber, D. A.
(2008). Increased Prevalence of EGFR-Mutant Lung Cancer in Women and in East Asian Populations: Analysis of Estrogen-Related Polymorphisms. Clin. Cancer Res.
14: 4079-4084
[Abstract][Full Text]
Fleming, I. N., Hogben, M., Frame, S., McClue, S. J., Green, S. R.
(2008). Synergistic Inhibition of ErbB Signaling by Combined Treatment with Seliciclib and ErbB-Targeting Agents. Clin. Cancer Res.
14: 4326-4335
[Abstract][Full Text]
Gonzales, A. J., Hook, K. E., Althaus, I. W., Ellis, P. A., Trachet, E., Delaney, A. M., Harvey, P. J., Ellis, T. A., Amato, D. M., Nelson, J. M., Fry, D. W., Zhu, T., Loi, C.-M., Fakhoury, S. A., Schlosser, K. M., Sexton, K. E., Winters, R. T., Reed, J. E., Bridges, A. J., Lettiere, D. J., Baker, D. A., Yang, J., Lee, H. T., Tecle, H., Vincent, P. W.
(2008). Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Molecular Cancer Therapeutics
7: 1880-1889
[Abstract][Full Text]
Dutt, A., Salvesen, H. B., Chen, T.-H., Ramos, A. H., Onofrio, R. C., Hatton, C., Nicoletti, R., Winckler, W., Grewal, R., Hanna, M., Wyhs, N., Ziaugra, L., Richter, D. J., Trovik, J., Engelsen, I. B., Stefansson, I. M., Fennell, T., Cibulskis, K., Zody, M. C., Akslen, L. A., Gabriel, S., Wong, K.-K., Sellers, W. R., Meyerson, M., Greulich, H.
(2008). Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl. Acad. Sci. USA
105: 8713-8717
[Abstract][Full Text]
Montagut, C., Sharma, S. V., Shioda, T., McDermott, U., Ulman, M., Ulkus, L. E., Dias-Santagata, D., Stubbs, H., Lee, D. Y., Singh, A., Drew, L., Haber, D. A., Settleman, J.
(2008). Elevated CRAF as a Potential Mechanism of Acquired Resistance to BRAF Inhibition in Melanoma. Cancer Res.
68: 4853-4861
[Abstract][Full Text]
Khuri, F. R., Roman, J.
(2008). From Nihilism to Individualism: The Evolution of Lung Cancer Therapy. Am. J. Respir. Crit. Care Med.
177: 1299-1300
[Full Text]
Ahn, M.-J., Park, B.-B., Ahn, J. S., Kim, S. W., Kim, H.-T., Lee, J. S., Kang, J. H., Cho, J. Y., Song, H. S., Park, S. H., Sohn, C. H., Shin, S. W., Choi, J. H., Ki, C.-S., Park, C. K., Holmes, A. J., Janne, P. A., Park, K.
(2008). Are There Any Ethnic Differences in Molecular Predictors of Erlotinib Efficacy in Advanced Non-Small Cell Lung Cancer?. Clin. Cancer Res.
14: 3860-3866
[Abstract][Full Text]
Felip, E., Rojo, F., Reck, M., Heller, A., Klughammer, B., Sala, G., Cedres, S., Peralta, S., Maacke, H., Foernzler, D., Parera, M., Mocks, J., Saura, C., Gatzemeier, U., Baselga, J.
(2008). A Phase II Pharmacodynamic Study of Erlotinib in Patients with Advanced Non-Small Cell Lung Cancer Previously Treated with Platinum-Based Chemotherapy. Clin. Cancer Res.
14: 3867-3874
[Abstract][Full Text]
Mayer, M.
(2008). Swimming Upstream: An Advocate Reflects on Cancer Research and Social Realities. JCO
26: 2783-2786
[Full Text]
Wordsworth, S, Buchanan, J, Papanicolas, I, Taylor, J, Frayling, I, Tomlinson, I
(2008). Molecular testing for somatic mutations in common cancers: the views of UK oncologists. J. Clin. Pathol.
61: 761-765
[Abstract][Full Text]
Velculescu, V. E.
(2008). Defining the blueprint of the cancer genome. Carcinogenesis
29: 1087-1091
[Abstract][Full Text]
Ikediobi, O. N., Reimers, M., Durinck, S., Blower, P. E., Futreal, A. P., Stratton, M. R., Weinstein, J. N.
(2008). In vitro differential sensitivity of melanomas to phenothiazines is based on the presence of codon 600 BRAF mutation. Molecular Cancer Therapeutics
7: 1337-1346
[Abstract][Full Text]
Lee, S. M., Buchler, T., Joseph, T., Lai, C.
(2008). Bilateral Eardrum Perforation After Long-Term Treatment With Erlotinib. JCO
26: 2582-2584
[Full Text]
Sequist, L. V., Martins, R. G., Spigel, D., Grunberg, S. M., Spira, A., Janne, P. A., Joshi, V. A., McCollum, D., Evans, T. L., Muzikansky, A., Kuhlmann, G. L., Han, M., Goldberg, J. S., Settleman, J., Iafrate, A. J., Engelman, J. A., Haber, D. A., Johnson, B. E., Lynch, T. J.
(2008). First-Line Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer Harboring Somatic EGFR Mutations. JCO
26: 2442-2449
[Abstract][Full Text]
Shepherd, F. A.
(2008). Molecular Selection of Patients for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer With Epidermal Growth Factor Inhibitors: Not Quite Ready for Prime Time. JCO
26: 2426-2427
[Full Text]
Engelman, J. A., Janne, P. A.
(2008). Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Clin. Cancer Res.
14: 2895-2899
[Abstract][Full Text]
Wainszelbaum, M. J., Charron, A. J., Kong, C., Kirkpatrick, D. S., Srikanth, P., Barbieri, M. A., Gygi, S. P., Stahl, P. D.
(2008). The Hominoid-specific Oncogene TBC1D3 Activates Ras and Modulates Epidermal Growth Factor Receptor Signaling and Trafficking. J. Biol. Chem.
283: 13233-13242
[Abstract][Full Text]
Mueller, K. L., Hunter, L. A., Ethier, S. P., Boerner, J. L.
(2008). Met and c-Src Cooperate to Compensate for Loss of Epidermal Growth Factor Receptor Kinase Activity in Breast Cancer Cells. Cancer Res.
68: 3314-3322
[Abstract][Full Text]
Li, A. R., Chitale, D., Riely, G. J., Pao, W., Miller, V. A., Zakowski, M. F., Rusch, V., Kris, M. G., Ladanyi, M.
(2008). EGFR Mutations in Lung Adenocarcinomas: Clinical Testing Experience and Relationship to EGFR Gene Copy Number and Immunohistochemical Expression. J. Mol. Diagn.
10: 242-248
[Abstract][Full Text]
Loriaux, M. M., Levine, R. L., Tyner, J. W., Frohling, S., Scholl, C., Stoffregen, E. P., Wernig, G., Erickson, H., Eide, C. A., Berger, R., Bernard, O. A., Griffin, J. D., Stone, R. M., Lee, B., Meyerson, M., Heinrich, M. C., Deininger, M. W., Gilliland, D. G., Druker, B. J.
(2008). High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia. Blood
111: 4788-4796
[Abstract][Full Text]
Jimeno, A., Tan, A. C., Coffa, J., Rajeshkumar, N.V., Kulesza, P., Rubio-Viqueira, B., Wheelhouse, J., Diosdado, B., Messersmith, W. A., Iacobuzio-Donahue, C., Maitra, A., Varella-Garcia, M., Hirsch, F. R., Meijer, G. A., Hidalgo, M.
(2008). Coordinated Epidermal Growth Factor Receptor Pathway Gene Overexpression Predicts Epidermal Growth Factor Receptor Inhibitor Sensitivity in Pancreatic Cancer. Cancer Res.
68: 2841-2849
[Abstract][Full Text]
Braun, B. S., Shannon, K.
(2008). Targeting Ras in Myeloid Leukemias. Clin. Cancer Res.
14: 2249-2252
[Abstract][Full Text]
Kato, T., Sato, N., Takano, A., Miyamoto, M., Nishimura, H., Tsuchiya, E., Kondo, S., Nakamura, Y., Daigo, Y.
(2008). Activation of Placenta-Specific Transcription Factor Distal-less Homeobox 5 Predicts Clinical Outcome in Primary Lung Cancer Patients. Clin. Cancer Res.
14: 2363-2370
[Abstract][Full Text]
Baker, S. D
(2008). Pharmacokinetic Considerations for Molecularly Targeted Therapy. aacredbook
2008: 705-709
[Abstract][Full Text]
Kumar, A., Petri, E. T., Halmos, B., Boggon, T. J.
(2008). Structure and Clinical Relevance of the Epidermal Growth Factor Receptor in Human Cancer. JCO
26: 1742-1751
[Abstract][Full Text]
Yatabe, Y., Takahashi, T., Mitsudomi, T.
(2008). Epidermal Growth Factor Receptor Gene Amplification Is Acquired in Association with Tumor Progression of EGFR-Mutated Lung Cancer. Cancer Res.
68: 2106-2111
[Abstract][Full Text]
Fuchs, B. C., Fujii, T., Dorfman, J. D., Goodwin, J. M., Zhu, A. X., Lanuti, M., Tanabe, K. K.
(2008). Epithelial-to-Mesenchymal Transition and Integrin-Linked Kinase Mediate Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Hepatoma Cells. Cancer Res.
68: 2391-2399
[Abstract][Full Text]
Godin-Heymann, N., Ulkus, L., Brannigan, B. W., McDermott, U., Lamb, J., Maheswaran, S., Settleman, J., Haber, D. A.
(2008). The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Molecular Cancer Therapeutics
7: 874-879
[Abstract][Full Text]
Gilbert, J. A., Goetz, M. P., Reynolds, C. A., Ingle, J. N., Giordano, K. F., Suman, V. J., Blair, H. E., Jenkins, R. B., Lingle, W. L., Reinholz, M. M., Adjei, A. A., Ames, M. M.
(2008). Molecular analysis of metaplastic breast carcinoma: high EGFR copy number via aneusomy. Molecular Cancer Therapeutics
7: 944-951
[Abstract][Full Text]
D'Addario, G., Rauch, D., Stupp, R., Pless, M., Stahel, R., Mach, N., Jost, L., Widmer, L., Tapia, C., Bihl, M., Mayer, M., Ribi, K., Lerch, S., Bubendorf, L., Betticher, D. C.
(2008). Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03. Ann Oncol
19: 739-745
[Abstract][Full Text]
Na, I. I., Byun, B. H., Kang, H. J., Cheon, G. J., Koh, J. S., Kim, C. H., Choe, D. H., Ryoo, B.-Y., Lee, J. C., Lim, S. M., Yang, S. H.
(2008). 18F-Fluoro-2-Deoxy-Glucose Uptake Predicts Clinical Outcome in Patients with Gefitinib-Treated Non-Small Cell Lung Cancer. Clin. Cancer Res.
14: 2036-2041
[Abstract][Full Text]
Smith, G D, Chadwick, B E, Willmore-Payne, C, Bentz, J S
(2008). Detection of epidermal growth factor receptor gene mutations in cytology specimens from patients with non-small cell lung cancer utilising high-resolution melting amplicon analysis. J. Clin. Pathol.
61: 487-493
[Abstract][Full Text]
Giovannetti, E., Lemos, C., Tekle, C., Smid, K., Nannizzi, S., Rodriguez, J. A., Ricciardi, S., Danesi, R., Giaccone, G., Peters, G. J.
(2008). Molecular Mechanisms Underlying the Synergistic Interaction of Erlotinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, with the Multitargeted Antifolate Pemetrexed in Non-Small-Cell Lung Cancer Cells. Mol. Pharmacol.
73: 1290-1300
[Abstract][Full Text]
Hezel, A. F., Zhu, A. X.
(2008). Systemic Therapy for Biliary Tract Cancers. The Oncologist
13: 415-423
[Abstract][Full Text]
Miller, V. A., Riely, G. J., Zakowski, M. F., Li, A. R., Patel, J. D., Heelan, R. T., Kris, M. G., Sandler, A. B., Carbone, D. P., Tsao, A., Herbst, R. S., Heller, G., Ladanyi, M., Pao, W., Johnson, D. H.
(2008). Molecular Characteristics of Bronchioloalveolar Carcinoma and Adenocarcinoma, Bronchioloalveolar Carcinoma Subtype, Predict Response to Erlotinib. JCO
26: 1472-1478
[Abstract][Full Text]
Jhawer, M., Goel, S., Wilson, A. J., Montagna, C., Ling, Y.-H., Byun, D.-S., Nasser, S., Arango, D., Shin, J., Klampfer, L., Augenlicht, L. H., Soler, R. P., Mariadason, J. M.
(2008). PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab. Cancer Res.
68: 1953-1961
[Abstract][Full Text]
Peipp, M., Schneider-Merck, T., Dechant, M., Beyer, T., Lammerts van Bueren, J. J., Bleeker, W. K., Parren, P. W. H. I., van de Winkel, J. G. J., Valerius, T.
(2008). Tumor Cell Killing Mechanisms of Epidermal Growth Factor Receptor (EGFR) Antibodies Are Not Affected by Lung Cancer-Associated EGFR Kinase Mutations. J. Immunol.
180: 4338-4345
[Abstract][Full Text]
Ciardiello, F., Tortora, G.
(2008). EGFR Antagonists in Cancer Treatment. NEJM
358: 1160-1174
[Full Text]
Yamashita, T., Forgues, M., Wang, W., Kim, J. W., Ye, Q., Jia, H., Budhu, A., Zanetti, K. A., Chen, Y., Qin, L.-X., Tang, Z.-Y., Wang, X. W.
(2008). EpCAM and {alpha}-Fetoprotein Expression Defines Novel Prognostic Subtypes of Hepatocellular Carcinoma. Cancer Res.
68: 1451-1461
[Abstract][Full Text]
Wordsworth, S, Papanicolas, I, Buchanan, J, Frayling, I, Taylor, J, Tomlinson, I
(2008). Molecular testing for somatic cancer mutations: a survey of current and future testing in UK laboratories. J. Clin. Pathol.
61: 373-376
[Abstract][Full Text]
Okabe, T., Okamoto, I., Tsukioka, S., Uchida, J., Iwasa, T., Yoshida, T., Hatashita, E., Yamada, Y., Satoh, T., Tamura, K., Fukuoka, M., Nakagawa, K.
(2008). Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase. Molecular Cancer Therapeutics
7: 599-606
[Abstract][Full Text]
Benedetti, V., Perego, P., Luca Beretta, G., Corna, E., Tinelli, S., Righetti, S. C., Leone, R., Apostoli, P., Lanzi, C., Zunino, F.
(2008). Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds. Molecular Cancer Therapeutics
7: 679-687
[Abstract][Full Text]
Pinter, F., Papay, J., Almasi, A., Sapi, Z., Szabo, E., Kanya, M., Tamasi, A., Jori, B., Varkondi, E., Moldvay, J., Szondy, K., Keri, G., Dominici, M., Conte, P., Eckhardt, S., Kopper, L., Schwab, R., Petak, I.
(2008). Epidermal Growth Factor Receptor (EGFR) High Gene Copy Number and Activating Mutations in Lung Adenocarcinomas Are Not Consistently Accompanied by Positivity for EGFR Protein by Standard Immunohistochemistry. J. Mol. Diagn.
10: 160-168
[Abstract][Full Text]
Black, P. C., Brown, G. A., Inamoto, T., Shrader, M., Arora, A., Siefker-Radtke, A. O., Adam, L., Theodorescu, D., Wu, X., Munsell, M. F., Bar-Eli, M., McConkey, D. J., Dinney, C. P.N.
(2008). Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells. Clin. Cancer Res.
14: 1478-1486
[Abstract][Full Text]
Fojo, T.
(2008). Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better. The Oncologist
13: 277-283
[Full Text]
Raponi, M., Lancet, J. E., Fan, H., Dossey, L., Lee, G., Gojo, I., Feldman, E. J., Gotlib, J., Morris, L. E., Greenberg, P. L., Wright, J. J., Harousseau, J.-L., Lowenberg, B., Stone, R. M., De Porre, P., Wang, Y., Karp, J. E.
(2008). A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia. Blood
111: 2589-2596
[Abstract][Full Text]
Lilenbaum, R., Axelrod, R., Thomas, S., Dowlati, A., Seigel, L., Albert, D., Witt, K., Botkin, D.
(2008). Randomized Phase II Trial of Erlotinib or Standard Chemotherapy in Patients With Advanced Non-Small-Cell Lung Cancer and a Performance Status of 2. JCO
26: 863-869
[Abstract][Full Text]
Eberhard, D. A., Giaccone, G., Johnson, B. E.
(2008). Biomarkers of Response to Epidermal Growth Factor Receptor Inhibitors in Non-Small-Cell Lung Cancer Working Group: Standardization for Use in the Clinical Trial Setting. JCO
26: 983-994
[Abstract][Full Text]
Aggarwal, S., Kim, S.-W., Ryu, S.-H., Chung, W.-C., Koo, J. S.
(2008). Growth Suppression of Lung Cancer Cells by Targeting Cyclic AMP Response Element-Binding Protein. Cancer Res.
68: 981-988
[Abstract][Full Text]
Brandes, A. A., Franceschi, E., Tosoni, A., Hegi, M. E., Stupp, R.
(2008). Epidermal Growth Factor Receptor Inhibitors in Neuro-oncology: Hopes and Disappointments. Clin. Cancer Res.
14: 957-960
[Abstract][Full Text]
Merchant, N. B., Voskresensky, I., Rogers, C. M., LaFleur, B., Dempsey, P. J., Graves-Deal, R., Revetta, F., Foutch, A. C., Rothenberg, M. L., Washington, M. K., Coffey, R. J.
(2008). TACE/ADAM-17: A Component of the Epidermal Growth Factor Receptor Axis and a Promising Therapeutic Target in Colorectal Cancer. Clin. Cancer Res.
14: 1182-1191
[Abstract][Full Text]
Tanaka, T., Munshi, A., Brooks, C., Liu, J., Hobbs, M. L., Meyn, R. E.
(2008). Gefitinib Radiosensitizes Non-Small Cell Lung Cancer Cells by Suppressing Cellular DNA Repair Capacity. Clin. Cancer Res.
14: 1266-1273
[Abstract][Full Text]
Tyner, J. W., Walters, D. K., Willis, S. G., Luttropp, M., Oost, J., Loriaux, M., Erickson, H., Corbin, A. S., O'Hare, T., Heinrich, M. C., Deininger, M. W., Druker, B. J.
(2008). RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia. Blood
111: 2238-2245
[Abstract][Full Text]
Yun, C.-H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K.-K., Meyerson, M., Eck, M. J.
(2008). The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc. Natl. Acad. Sci. USA
105: 2070-2075
[Abstract][Full Text]
Ogawa, E., Takenaka, K., Katakura, H., Adachi, M., Otake, Y., Toda, Y., Kotani, H., Manabe, T., Wada, H., Tanaka, F.
(2008). Perimembrane Aurora-A Expression is a Significant Prognostic Factor in Correlation with Proliferative Activity in Non-Small-Cell Lung Cancer (NSCLC). Ann. Surg. Oncol.
15: 547-554
[Abstract][Full Text]
Lin, W. M., Baker, A. C., Beroukhim, R., Winckler, W., Feng, W., Marmion, J. M., Laine, E., Greulich, H., Tseng, H., Gates, C., Hodi, F. S., Dranoff, G., Sellers, W. R., Thomas, R. K., Meyerson, M., Golub, T. R., Dummer, R., Herlyn, M., Getz, G., Garraway, L. A.
(2008). Modeling Genomic Diversity and Tumor Dependency in Malignant Melanoma. Cancer Res.
68: 664-673
[Abstract][Full Text]
Cavazzoni, A., Alfieri, R. R., Carmi, C., Zuliani, V., Galetti, M., Fumarola, C., Frazzi, R., Bonelli, M., Bordi, F., Lodola, A., Mor, M., Petronini, P. G.
(2008). Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines. Molecular Cancer Therapeutics
7: 361-370
[Abstract][Full Text]
Wang, S., Guo, P., Wang, X., Zhou, Q., Gallo, J. M.
(2008). Preclinical pharmacokinetic/pharmacodynamic models of gefitinib and the design of equivalent dosing regimens in EGFR wild-type and mutant tumor models. Molecular Cancer Therapeutics
7: 407-417
[Abstract][Full Text]
Contessa, J. N., Hamstra, D. A.
(2008). Revoking the Privilege: Targeting HER2 in the Central Nervous System. Mol. Pharmacol.
73: 271-273
[Abstract][Full Text]
Gridelli, C., Maione, P., Rossi, A.
(2008). The Potential Role of mTOR Inhibitors in Non-Small Cell Lung Cancer. The Oncologist
13: 139-147
[Abstract][Full Text]
Kuwai, T., Nakamura, T., Kim, S.-J., Sasaki, T., Kitadai, Y., Langley, R. R., Fan, D., Hamilton, S. R., Fidler, I. J.
(2008). Intratumoral Heterogeneity for Expression of Tyrosine Kinase Growth Factor Receptors in Human Colon Cancer Surgical Specimens and Orthotopic Tumors. Am. J. Pathol.
172: 358-366
[Abstract][Full Text]
Fan, Y.-X., Wong, L., Ding, J., Spiridonov, N. A., Johnson, R. C., Johnson, G. R.
(2008). Mutational Activation of ErbB2 Reveals a New Protein Kinase Autoinhibition Mechanism. J. Biol. Chem.
283: 1588-1596
[Abstract][Full Text]
Wong, D. J., Nuyten, D. S.A., Regev, A., Lin, M., Adler, A. S., Segal, E., van de Vijver, M. J., Chang, H. Y.
(2008). Revealing Targeted Therapy for Human Cancer by Gene Module Maps. Cancer Res.
68: 369-378
[Abstract][Full Text]
Gilmer, T. M., Cable, L., Alligood, K., Rusnak, D., Spehar, G., Gallagher, K. T., Woldu, E., Carter, H. L., Truesdale, A. T., Shewchuk, L., Wood, E. R.
(2008). Impact of Common Epidermal Growth Factor Receptor and HER2 Variants on Receptor Activity and Inhibition by Lapatinib. Cancer Res.
68: 571-579
[Abstract][Full Text]
Sawai, A., Chandarlapaty, S., Greulich, H., Gonen, M., Ye, Q., Arteaga, C. L., Sellers, W., Rosen, N., Solit, D. B.
(2008). Inhibition of Hsp90 Down-regulates Mutant Epidermal Growth Factor Receptor (EGFR) Expression and Sensitizes EGFR Mutant Tumors to Paclitaxel. Cancer Res.
68: 589-596
[Abstract][Full Text]
Guo, A., Villen, J., Kornhauser, J., Lee, K. A., Stokes, M. P., Rikova, K., Possemato, A., Nardone, J., Innocenti, G., Wetzel, R., Wang, Y., MacNeill, J., Mitchell, J., Gygi, S. P., Rush, J., Polakiewicz, R. D., Comb, M. J.
(2008). Signaling networks assembled by oncogenic EGFR and c-Met. Proc. Natl. Acad. Sci. USA
105: 692-697
[Abstract][Full Text]
Tanabe, K. K., Lemoine, A., Finkelstein, D. M., Kawasaki, H., Fujii, T., Chung, R. T., Lauwers, G. Y., Kulu, Y., Muzikansky, A., Kuruppu, D., Lanuti, M., Goodwin, J. M., Azoulay, D., Fuchs, B. C.
(2008). Epidermal Growth Factor Gene Functional Polymorphism and the Risk of Hepatocellular Carcinoma in Patients With Cirrhosis. JAMA
299: 53-60
[Abstract][Full Text]
Sarkaria, I. S., Zakowski, M. F., Pham, D., Hezel, M., Ebright, M. I., Chuai, S., Venkatraman, E. S., Kris, M. G., Rusch, V. W., Singh, B.
(2008). Epidermal Growth Factor Receptor Signaling in Adenocarcinomas With Bronchioloalveolar Components. Ann. Thorac. Surg.
85: 216-223
[Abstract][Full Text]
Reznik, T. E., Sang, Y., Ma, Y., Abounader, R., Rosen, E. M., Xia, S., Laterra, J.
(2008). Transcription-Dependent Epidermal Growth Factor Receptor Activation by Hepatocyte Growth Factor. Mol Cancer Res
6: 139-150
[Abstract][Full Text]
Duffy, A., Kortmansky, J., Schwartz, G. K., Capanu, M., Puleio, S., Minsky, B., Saltz, L., Kelsen, D. P., O'Reilly, E. M.
(2008). A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma. Ann Oncol
19: 86-91
[Abstract][Full Text]
Gow, C.-H., Chien, C.-R., Chang, Y.-L., Chiu, Y.-H., Kuo, S.-H., Shih, J.-Y., Chang, Y.-C., Yu, C.-J., Yang, C.-H., Yang, P.-C.
(2008). Radiotherapy in Lung Adenocarcinoma with Brain Metastases: Effects of Activating Epidermal Growth Factor Receptor Mutations on Clinical Response. Clin. Cancer Res.
14: 162-168
[Abstract][Full Text]
Bunn, P. A. Jr., Thatcher, N.
(2008). Introduction. The Oncologist
13: 1-4
[Abstract][Full Text]
de Marinis, F., Grossi, F.
(2008). Clinical Evidence for Second- and Third-Line Treatment Options in Advanced Non-Small Cell Lung Cancer. The Oncologist
13: 14-20
[Abstract][Full Text]
Bean, J., Brennan, C., Shih, J.-Y., Riely, G., Viale, A., Wang, L., Chitale, D., Motoi, N., Szoke, J., Broderick, S., Balak, M., Chang, W.-C., Yu, C.-J., Gazdar, A., Pass, H., Rusch, V., Gerald, W., Huang, S.-F., Yang, P.-C., Miller, V., Ladanyi, M., Yang, C.-H., Pao, W.
(2007). MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc. Natl. Acad. Sci. USA
104: 20932-20937
[Abstract][Full Text]
Butts, C. A., Bodkin, D., Middleman, E. L., Englund, C. W., Ellison, D., Alam, Y., Kreisman, H., Graze, P., Maher, J., Ross, H. J., Ellis, P. M., McNulty, W., Kaplan, E., Pautret, V., Weber, M. R., Shepherd, F. A.
(2007). Randomized Phase II Study of Gemcitabine Plus Cisplatin or Carboplatin, With or Without Cetuximab, As First-Line Therapy for Patients With Advanced or Metastatic Non-Small-Cell Lung Cancer. JCO
25: 5777-5784
[Abstract][Full Text]
Yoshida, Y., Kokubu, A., Suzuki, K., Kuribayashi, H., Tsuta, K., Matsuno, Y., Kusumoto, M., Kanai, Y., Asamura, H., Hirohashi, S., Shibata, T.
(2007). Molecular Markers and Changes of Computed Tomography Appearance in Lung Adenocarcinoma with Ground-grass Opacity. Jpn J Clin Oncol
0: hym139v1-6
[Abstract][Full Text]
Deng, J., Shimamura, T., Perera, S., Carlson, N. E., Cai, D., Shapiro, G. I., Wong, K.-K., Letai, A.
(2007). Proapoptotic BH3-Only BCL-2 Family Protein BIM Connects Death Signaling from Epidermal Growth Factor Receptor Inhibition to the Mitochondrion. Cancer Res.
67: 11867-11875
[Abstract][Full Text]
Previous
