Human Molecular Genetics Advance Access published online on October 20, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh331
© 2004 by Oxford University Press
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-Ward, Tokyo 108-8639, Japan; Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima School of Medicine, Tokushima-City, Tokushima 770-8503, Japan
* To whom correspondence should be addressed. Gefitinib (Iressa, ZD1839), an inhibitor of epidermal growth factor receptor-tyrosine kinase (EGFR-TK), has shown potent anti-tumor effects and improved symptom and quality-of-life of a subset of patients with advanced NSCLC. However, a large portion of the patients showed no effect to this agent. To establish a method to predict the response of NSCLC patients to gefitinib, we used a genome-wide cDNA microarray to analyze 33 biopsy samples of advanced NSCLC from patients who had been treated with an identical protocol of second- to 7th-line gefitinib monotherapy. We identified 51 genes whose expression differed significantly between 7 responders and 10 non-responders to the drug. We selected the 12 genes that showed the most significant differences to establish a numerical scoring system (GRS, gefitinib response score), for predicting response to gefitinib treatment. The GRS system clearly separated the two groups without any overlap, and accurately predicted responses to the drug in sixteen additional NSCLC cases. The system was further validated by the semi-quantitative RT-PCR, immunohistochemistry, and ELISA for serological test. Moreover, we proved that the anti-apoptotic activity of amphiregulin (AREG), a protein that was significantly over-expressed in non-responders but undetectable in responders, leads to resistance of NSCLC cells to gefitinib in vitro. Our results suggested that sensitivity of a given NSCLC to gefitinib can be predicted according to expression levels of a defined set of genes that may biologically affect drug sensitivity and survival of lung-cancer cells. Our scoring system might eventually lead to achievement of personalized therapy for NSCLC patients.
Article
Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839)
2 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-Ward, Tokyo 108-8639, Japan
3 Laboratory for Medical Informatics, SNP Research Center, Riken (Institute of Physical and Chemical Research), Yokohama-City, Kanagawa 230-0045, Japan
4 Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima School of Medicine, Tokushima-City, Tokushima 770-8503, Japan
5 Department of Medical Oncology, Kinki University School of Medicine, Osaka-Sayama-City, Osaka 589-8511, Japan
6 Laboratory of Cell Growth and Regulation, Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-Ward, Tokyo 113-0032, Japan
7 Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima-City, Hiroshima 734-8551, Japan
8 Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-Ward, Minato-ku, Tokyo 108-8639, Japan
Yusuke Nakamura, E-mail: yusuke{at}ims.u-tokyo.ac.jp
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. L. Sheng, G. Huang, B. Yu, and W. X. Qin Clinical Significance and Prognostic Value of Serum Dickkopf-1 Concentrations in Patients with Lung Cancer Clin. Chem., September 1, 2009; 55(9): 1656 - 1664. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Takano, N. Ishikawa, R. Nishino, K. Masuda, W. Yasui, K. Inai, H. Nishimura, H. Ito, H. Nakayama, Y. Miyagi, et al. Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer Cancer Res., August 15, 2009; 69(16): 6694 - 6703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sun, C. Behrens, L. Feng, N. Ozburn, X. Tang, G. Yin, R. Komaki, M. Varella-Garcia, W. K. Hong, K. D. Aldape, et al. HER Family Receptor Abnormalities in Lung Cancer Brain Metastases and Corresponding Primary Tumors Clin. Cancer Res., August 1, 2009; 15(15): 4829 - 4837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Hirata, T. Yamabuki, D. Miki, T. Ito, E. Tsuchiya, M. Fujita, M. Hosokawa, K. Chayama, Y. Nakamura, and Y. Daigo Involvement of Epithelial Cell Transforming Sequence-2 Oncoantigen in Lung and Esophageal Cancer Progression Clin. Cancer Res., January 1, 2009; 15(1): 256 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. McGowan, E. McKiernan, F. Bolster, B. M. Ryan, A. D. K. Hill, E. W. McDermott, D. Evoy, N. O'Higgins, J. Crown, and M. J. Duffy ADAM-17 predicts adverse outcome in patients with breast cancer Ann. Onc., June 1, 2008; 19(6): 1075 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kato, N. Sato, A. Takano, M. Miyamoto, H. Nishimura, E. Tsuchiya, S. Kondo, Y. Nakamura, and Y. Daigo Activation of Placenta-Specific Transcription Factor Distal-less Homeobox 5 Predicts Clinical Outcome in Primary Lung Cancer Patients Clin. Cancer Res., April 15, 2008; 14(8): 2363 - 2370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Stearman, L. Dwyer-Nield, M. C. Grady, A. M. Malkinson, and M. W. Geraci A Macrophage Gene Expression Signature Defines a Field Effect in the Lung Tumor Microenvironment Cancer Res., January 1, 2008; 68(1): 34 - 43. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ishikawa, A. Takano, W. Yasui, K. Inai, H. Nishimura, H. Ito, Y. Miyagi, H. Nakayama, M. Fujita, M. Hosokawa, et al. Cancer-Testis Antigen Lymphocyte Antigen 6 Complex Locus K Is a Serologic Biomarker and a Therapeutic Target for Lung and Esophageal Carcinomas Cancer Res., December 15, 2007; 67(24): 11601 - 11611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Taniwaki, A. Takano, N. Ishikawa, W. Yasui, K. Inai, H. Nishimura, E. Tsuchiya, N. Kohno, Y. Nakamura, and Y. Daigo Activation of KIF4A as a Prognostic Biomarker and Therapeutic Target for Lung Cancer Clin. Cancer Res., November 15, 2007; 13(22): 6624 - 6631. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Minna, L. Girard, and Y. Xie Tumor mRNA Expression Profiles Predict Responses to Chemotherapy J. Clin. Oncol., October 1, 2007; 25(28): 4329 - 4336. [Full Text] [PDF]
|
|
|
|
|
|
S. Hayama, Y. Daigo, T. Yamabuki, D. Hirata, T. Kato, M. Miyamoto, T. Ito, E. Tsuchiya, S. Kondo, and Y. Nakamura Phosphorylation and Activation of Cell Division Cycle Associated 8 by Aurora Kinase B Plays a Significant Role in Human Lung Carcinogenesis Cancer Res., May 1, 2007; 67(9): 4113 - 4122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Raponi, J.-L. Harousseau, J. E. Lancet, B. Lowenberg, R. Stone, Y. Zhang, W. Rackoff, Y. Wang, and D. Atkins Identification of Molecular Predictors of Response in a Study of Tipifarnib Treatment in Relapsed and Refractory Acute Myelogenous Leukemia Clin. Cancer Res., April 1, 2007; 13(7): 2254 - 2260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamabuki, A. Takano, S. Hayama, N. Ishikawa, T. Kato, M. Miyamoto, T. Ito, H. Ito, Y. Miyagi, H. Nakayama, et al. Dikkopf-1 as a Novel Serologic and Prognostic Biomarker for Lung and Esophageal Carcinomas Cancer Res., March 15, 2007; 67(6): 2517 - 2525. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Suzuki, K. Takahashi, S. Hayama, N. Ishikawa, T. Kato, T. Ito, E. Tsuchiya, Y. Nakamura, and Y. Daigo Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer Mol. Cancer Ther., February 1, 2007; 6(2): 542 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Okano, T. Kondo, K. Fujii, T. Nishimura, T. Takano, Y. Ohe, K. Tsuta, Y. Matsuno, A. Gemma, H. Kato, et al. Proteomic Signature Corresponding to the Response to Gefitinib (Iressa, ZD1839), an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma Clin. Cancer Res., February 1, 2007; 13(3): 799 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kato, S. Hayama, T. Yamabuki, N. Ishikawa, M. Miyamoto, T. Ito, E. Tsuchiya, S. Kondo, Y. Nakamura, and Y. Daigo Increased Expression of Insulin-like Growth Factor-II Messenger RNA-Binding Protein 1 Is Associated with Tumor Progression in Patients with Lung Cancer Clin. Cancer Res., January 15, 2007; 13(2): 434 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Campbell, C. A. Zanta, L. J. Heyer, B. Kittinger, K. M. Gabric, and L. Adler DNA Microarray Wet Lab Simulation Brings Genomics into the High School Curriculum CBE Life Sci Educ, December 1, 2006; 5(4): 332 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yan, Y. Lu, M. Wang, H. Vikis, R. Yao, Y. Wang, R. A. Lubet, and M. You Effect of an Epidermal Growth Factor Receptor Inhibitor in Mouse Models of Lung Cancer Mol. Cancer Res., December 1, 2006; 4(12): 971 - 981. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Takahashi, C. Furukawa, A. Takano, N. Ishikawa, T. Kato, S. Hayama, C. Suzuki, W. Yasui, K. Inai, S. Sone, et al. The Neuromedin U-Growth Hormone Secretagogue Receptor 1b/Neurotensin Receptor 1 Oncogenic Signaling Pathway as a Therapeutic Target for Lung Cancer Cancer Res., October 1, 2006; 66(19): 9408 - 9419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-Y. Sung, H. Kubo, K. Shigemura, R. S. Arnold, S. Logani, R. Wang, H. Konaka, M. Nakagawa, S. Mousses, M. Amin, et al. Oxidative Stress Induces ADAM9 Protein Expression in Human Prostate Cancer Cells Cancer Res., October 1, 2006; 66(19): 9519 - 9526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Carey, A. J. Garton, M. S. Romero, J. Kahler, S. Thomson, S. Ross, F. Park, J. D. Haley, N. Gibson, and M. X. Sliwkowski Kinetic Analysis of Epidermal Growth Factor Receptor Somatic Mutant Proteins Shows Increased Sensitivity to the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib Cancer Res., August 15, 2006; 66(16): 8163 - 8171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kalyankrishna and J. R. Grandis Epidermal Growth Factor Receptor Biology in Head and Neck Cancer J. Clin. Oncol., June 10, 2006; 24(17): 2666 - 2672. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Suzuki, Y. Daigo, N. Ishikawa, T. Kato, S. Hayama, T. Ito, E. Tsuchiya, and Y. Nakamura ANLN Plays a Critical Role in Human Lung Carcinogenesis through the Activation of RHOA and by Involvement in the Phosphoinositide 3-Kinase/AKT Pathway Cancer Res., December 15, 2005; 65(24): 11314 - 11325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ishikawa, Y. Daigo, A. Takano, M. Taniwaki, T. Kato, S. Hayama, H. Murakami, Y. Takeshima, K. Inai, H. Nishimura, et al. Increases of Amphiregulin and Transforming Growth Factor-{alpha} in Serum as Predictors of Poor Response to Gefitinib among Patients with Advanced Non-Small Cell Lung Cancers Cancer Res., October 15, 2005; 65(20): 9176 - 9184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Furukawa, Y. Daigo, N. Ishikawa, T. Kato, T. Ito, E. Tsuchiya, S. Sone, and Y. Nakamura Plakophilin 3 Oncogene as Prognostic Marker and Therapeutic Target for Lung Cancer Cancer Res., August 15, 2005; 65(16): 7102 - 7110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. French, M. R. Wilkinson, W. Yang, L. de Chaisemartin, E. H. Cook, S. Das, M. J. Ratain, W. E. Evans, J. R. Downing, C.-H. Pui, et al. Global gene expression as a function of germline genetic variation Hum. Mol. Genet., June 15, 2005; 14(12): 1621 - 1629. [Abstract] [Full Text] [PDF]
|
|