Prediction of sensitivity of advanced non-small cell lung cancers to gefitinib (Iressa, ZD1839).

Gefitinib (Iressa, ZD1839), an inhibitor of epidermal growth factor receptor-tyrosine kinase, has shown potent anti-tumor effects and improved symptoms and quality-of-life of a subset of patients with advanced non-small cell lung cancer (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 seventh line gefitinib monotherapy. We identified 51 genes whose expression differed significantly between seven 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 16 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, 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.

[1]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[2]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[3]  William Pao,et al.  Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Yusuke Nakamura,et al.  Prediction of response to neoadjuvant chemotherapy for osteosarcoma by gene-expression profiles. , 2004, International journal of oncology.

[5]  J. Coll,et al.  Inhibition of Apoptosis by Amphiregulin via an Insulin‐like Growth Factor‐1 Receptor—Dependent Pathway in Non‐Small Cell Lung Cancer Cell Lines , 2003, Annals of the New York Academy of Sciences.

[6]  David Cella,et al.  Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. , 2003, JAMA.

[7]  Yusuke Nakamura,et al.  Gene-expression profiles of human tumor xenografts in nude mice treated orally with the EGFR tyrosine kinase inhibitor ZD1839. , 2003, International journal of oncology.

[8]  Masahiro Fukuoka,et al.  Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Yusuke Nakamura,et al.  Genome-wide analysis of organ-preferential metastasis of human small cell lung cancer in mice. , 2003, Molecular cancer research : MCR.

[10]  Yusuke Nakamura,et al.  Expression profiles of non-small cell lung cancers on cDNA microarrays: Identification of genes for prediction of lymph-node metastasis and sensitivity to anti-cancer drugs , 2003, Oncogene.

[11]  P. Traxler,et al.  Tyrosine kinases as targets in cancer therapy – successes and failures , 2003, Expert opinion on therapeutic targets.

[12]  R. Herbst.  Dose-comparative monotherapy trials of ZD1839 in previously treated non-small cell lung cancer patients. , 2003, Seminars in oncology.

[13]  M. Ebina,et al.  Severe acute interstitial pneumonia and gefitinib , 2003, The Lancet.

[14]  J. Coll,et al.  Inhibition of Apoptosis by Amphiregulin via an Insulin-like Growth Factor-1 Receptor-dependent Pathway in Non-small Cell Lung Cancer Cell Lines* , 2002, The Journal of Biological Chemistry.

[15]  M. Kris,et al.  Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma. , 2002, The Annals of thoracic surgery.

[16]  K. Gibson,et al.  ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. , 2002, Cancer research.

[17]  David L. Brautigan,et al.  The Specificity of Extracellular Signal-regulated Kinase 2 Dephosphorylation by Protein Phosphatases* , 2002, The Journal of Biological Chemistry.

[18]  David E. Misek,et al.  Gene-expression profiles predict survival of patients with lung adenocarcinoma , 2002, Nature Medicine.

[19]  J. Baselga.  Why the epidermal growth factor receptor? The rationale for cancer therapy. , 2002, The oncologist.

[20]  David Elashoff,et al.  Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study , 2002, The Lancet.

[21]  C. Begley,et al.  An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells , 2002, Oncogene.

[22]  David Harrington,et al.  Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. , 2002, The New England journal of medicine.

[23]  J. Crowley,et al.  Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[25]  E. Cheng,et al.  Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1. , 2000, Molecular cell.

[26]  M. Kris,et al.  Randomized Phase III Trial of Docetaxel Versus Vinorelbine or Ifosfamide in Patients With Advanced Non–Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy Regimens , 2000 .

[27]  R. Derynck,et al.  The Tetraspanin Cd9 Associates with Transmembrane TGF-α and Regulates TGF-α–Induced Egf Receptor Activation and Cell Proliferation , 2000, The Journal of cell biology.

[28]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[29]  D. Blake,et al.  Overexpression of the regulatory subunit of gamma-glutamylcysteine synthetase in HeLa cells increases gamma-glutamylcysteine synthetase activity and confers drug resistance. , 1999, The Biochemical journal.

[30]  K. Schütze,et al.  Microbeam MOMeNT: non-contact laser microdissection of membrane-mounted native tissue. , 1997, The American journal of pathology.

[31]  O. Brodin,et al.  Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials , 1995 .

[32]  N. Hanna.  Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways , 2006 .

[33]  J. Sudbø,et al.  Gene-expression profiles in hereditary breast cancer. , 2001, The New England journal of medicine.

[34]  M. Kris,et al.  Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  A. Ullrich,et al.  EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF , 1999, Nature.

[36]  C. Angeletti,et al.  Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.