Integrin beta1 over‐expression associates with resistance to tyrosine kinase inhibitor gefitinib in non‐small cell lung cancer

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as gefitinib and erlotinib have been widely used in treating patients with advanced non‐small cell lung cancer (NSCLC). However, acquired resistance to EGFR TKI almost occurs in every patient eventually. To identify its potential mechanism, we established a human NSCLC cell line PC9/AB2 which was 576‐fold decrease in gefitinib sensitivity compared with its parental PC9 cell lines. No EGFR‐T790M mutation or abnormal expression of c‐Met protein was found in PC9/AB2 cells. Over‐expression of integrin β1 was found, accompanied with increase of the cells' adhesion and migration. To further confirm the role of integrin β1 in gefitinib acquired resistance, we transferred its siRNA‐expressing plasmid and its whole cDNA expressing plasmid into PC9/AB2 and into PC9 cells, respectively. The sensitivity of NSCLC cells to gefitinib was negatively correlated with integrin β1 expression levels. All these data suggest that up‐regulation of integrin β1 might be an important factor for gefitinib resistance in NSCLC cell line PC9/AB2. J. Cell. Biochem. 111: 1565–1574, 2010. © 2010 Wiley‐Liss, Inc.

[1]  S. Toyooka,et al.  Establishment and molecular characteristics of PC-9 derived erlotinib resistant cell lines. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  B. Mehić,et al.  Our experiences with erlotinib in second and third line treatment patients with advanced stage IIIB/ IV non-small cell lung cancer. , 2008, Bosnian journal of basic medical sciences.

[3]  S. Johansson,et al.  EGFR and beta1 integrins utilize different signaling pathways to activate Akt. , 2008, Experimental cell research.

[4]  William Pao,et al.  MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib , 2007, Proceedings of the National Academy of Sciences.

[5]  K. Kiura,et al.  Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non small cell lung cancer cell line. , 2007, Cancer research.

[6]  L. Paz-Ares,et al.  Setting the benchmark for tailoring treatment with EGFR tyrosine kinase inhibitors. , 2007, Future oncology.

[7]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[8]  Matthew Meyerson,et al.  Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. , 2007, Cancer cell.

[9]  Daniel A. Haber,et al.  Epidermal growth factor receptor mutations in lung cancer , 2007, Nature Reviews Cancer.

[10]  K. Matsuo,et al.  Prospective Validation for Prediction of Gefitinib Sensitivity by Epidermal Growth Factor Receptor Gene Mutation in Patients with Non-Small Cell Lung Cancer , 2007, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[11]  A. MacKinnon,et al.  Extracellular matrix regulation of drug resistance in small-cell lung cancer , 2007, International journal of radiation biology.

[12]  K. Hagiwara,et al.  Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp , 2006, British Journal of Cancer.

[13]  P. Jänne,et al.  Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. , 2006, The Journal of clinical investigation.

[14]  M. Maemondo,et al.  Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  M. Meyerson,et al.  Exon 19 Deletion Mutations of Epidermal Growth Factor Receptor Are Associated with Prolonged Survival in Non–Small Cell Lung Cancer Patients Treated with Gefitinib or Erlotinib , 2006, Clinical Cancer Research.

[16]  L. Layfield,et al.  Detection of EGFR- and HER2-activating mutations in squamous cell carcinoma involving the head and neck , 2006, Modern Pathology.

[17]  T. Čufer,et al.  Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer , 2006, Anti-cancer drugs.

[18]  Patricia L. Harris,et al.  Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  N. Saijo,et al.  Establishment of a human non‐small cell lung cancer cell line resistant to gefitinib , 2005, International journal of cancer.

[20]  Patricia L. Harris,et al.  Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Meyerson,et al.  EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. , 2005, The New England journal of medicine.

[22]  H. Varmus,et al.  Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain , 2005, PLoS medicine.

[23]  Yu Jin,et al.  Ganoderma lucidum extracts inhibit growth and induce actin polymerization in bladder cancer cells in vitro. , 2004, Cancer letters.

[24]  Masahiro Fukuoka,et al.  Gefitinib — a novel targeted approach to treating cancer , 2004, Nature Reviews Cancer.

[25]  A. Paradiso,et al.  Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells , 2004, British Journal of Cancer.

[26]  Joachim Herz,et al.  Mutations and addiction to EGFR: the Achilles 'heal' of lung cancers? , 2004, Trends in molecular medicine.

[27]  V. Rao,et al.  Epidermal Growth Factor Receptor-Dependent Regulation of Integrin-Mediated Signaling and Cell Cycle Entry in Epithelial Cells , 2004, Molecular and Cellular Biology.

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

[29]  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.

[30]  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.

[31]  R. Nicholson,et al.  EGFR and cancer prognosis. , 2001, European journal of cancer.

[32]  N. Normanno,et al.  Epidermal growth factor-related peptides and their receptors in human malignancies. , 1995, Critical reviews in oncology/hematology.

[33]  R. Katakura,et al.  Detection of p53 gene mutations in human brain tumors by single-strand conformation polymorphism analysis of polymerase chain reaction products. , 1991, Oncogene.

[34]  S. Rodenhuis,et al.  The ras oncogenes in human lung cancer. , 1990, The American review of respiratory disease.

[35]  S. Rodenhuis,et al.  Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. , 1988, Cancer research.

[36]  E. Berns,et al.  Integrated genomics of chemotherapy resistant ovarian cancer: a role for extracellular matrix, TGFbeta and regulating microRNAs. , 2010, The international journal of biochemistry & cell biology.

[37]  Z. Cai-cun.  Selection and establishment of gefitinib-resistant PC9 cell line and its gene expression profile , 2008 .

[38]  須谷 顕尚.  Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp , 2007 .

[39]  T. Sekiya,et al.  Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. , 1990, Oncogene.