Source: International Congress 2014 – Pathology and prognostic factors of thoracic tumours
Disease area: Thoracic oncology

Abstract

EGF receptor (EGFR) tyrosine kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non-small cell lung cancers (NSCLC) harboring EGFR-activating mutations. However, most patients ultimately develop resistance to these drugs. Here, we report two kinds of mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors. In this study, we established gefitinib or erlotinib-resistant NSCLC cells from PC-9 cell line harboring del EGFR mutation. In gefitinib-resistant lung cancer cells, they showed a marked downregulation of PTEN expression and increased Akt phosphorylation. Knockdown of PTEN expression using small interfering RNA specific for PTEN in PC-9 cells resulted in drug resistance to gefitinib and erlotinib. Reduced PTEN expression was also observed in tumor samples from patients with gefitinib-refractory NSCLC. On the other hand, in erlotinib-resistant lung cancer cells, they showed marked expressions of Src, integrin beta 1, alpha 2, and alpha 5 along with enhanced cell adhesion activity. RNAi-mediated silencing of integrin beta 1 restored erlotinib sensitivity and reduced activation of Src and Akt after erlotinib treatment. Increased expression of integrin beta 1, alpha 5, and/or alpha 2 was also observed in tumor samples from patients with lung cancer treated with erlotinib and/or gefitinib. Together, we present our novel two mechanisms, PTEN loss and integrin beta 1/Src activation, involving acquired resistance to EGFR TKI in lung cancer cells. Our findings suggested that acquired Akt activation by a variety of ways contributes to gefitinib and erlotinib resistance in NSCLC.

Rating:

Share or cite this content

Citations should be made in the following way:
H. Izumi, R. Kanda, Y. Murakami, Y. Morimoto, M. Ono (Kitakyushu, Fukuoka, Japan). Novel two mechanisms for acquired EGFR-TKI resistance in lung cancer cells harboring EGFR activating mutation. Eur Respir J 2014; 44: Suppl. 58, 508

Member's Comments

No comment yet.

Related content which might interest you: RBM5 overexpression reverses acquired resistance to gefitinib in PC9/AB2 NSCLC cells Source: International Congress 2016 – Late-breaking translational research in lung cancer Year: 2016 Unexpected hair growth induced by gefitinib treatment in two patients with EGFR gene mutation-positive adenocarcinoma of the lung Source: International Congress 2015 – Diagnosis and therapy of lung cancer Year: 2015 EGFR mutations determine EGFR-MET crosstalk and MET inhibition in lung cancer Source: International Congress 2015 – Biomarkers, immunology and molecular pathology of lung cancer Year: 2015 Simultaneous EGFR and VEGF alterations in non-small cell lung carcinoma based on tissue microarrays Source: International Congress 2014 – Pathology and prognostic factors of thoracic tumours Year: 2014 CD33+CD14-CD11b+CD66b+CD15+VEGFR-1hi myeloid derived suppressor cells and their clinical relevance in non-small cell lung cancer Source: International Congress 2014 – Biology and pathology of thoracic tumours Year: 2014 Met amplification induces an aggressive phenotype in EGFR tyrosine kinase inhibitors resistant non-small-cell lung cancer Source: International Congress 2015 – New frontiers in biomedical research on thoracic tumours Year: 2015 Cytological samples for the study of EGFR, KRAS and ALK mutations in non-small cell lung cancer Source: Annual Congress 2013 –Progress in bronchoscopy and pathology techniques for diagnosis of thoracic malignancies Year: 2013 Antitumor efficacy of the double suicide genesin lung cancer cells Source: International Congress 2015 – Cell biology of lung cancer and new biomarkers Year: 2015 Significance of EGFR expression patterns in patients with non-small cell lung cancer – Evaluation on protein- and/or gene level? Source: International Congress 2014 – Pathology and prognostic factors of thoracic tumours Year: 2014 EGFRmutations are associated with higher brain metastasis radio-sensitivity than KRAS mutations or wild type EGFR in non-small cell lung cancer patients (NSCLC) Source: International Congress 2014 – Therapy of thoracic tumours: clinical trials and case series Year: 2014 Frequency and type of EGFR mutations in patients with adenocarcinoma of the lung Source: Annual Congress 2013 –Prognostic factors and subtyping of lung cancer Year: 2013 Metabolic modification as a potential therapeutics approach in lung cancer Source: Annual Congress 2013 –Systemic therapy of lung cancer and quality of life Year: 2013 Gene expression of EGFR, MINA53,MEN1 and MTOR in NSCLCs Source: International Congress 2014 – Biology and pathology of thoracic tumours Year: 2014 A requirement for IKKa in lung adenocarcinoma Source: International Congress 2015 – Cell biology of lung cancer and new biomarkers Year: 2015 Lung cancer patients harbouring epidermal growth factor receptor mutation Source: International Congress 2015 – Lung cancer: prognostic factors and features of oncogene-driven tumours Year: 2015 Simvastatin overcomes gefitinib resistance in non-small cell lung cancer with the T790M mutation of epidermal growth factor receptor via Akt/b-catenin signaling dependent down-regulation of survivin Source: Annual Congress 2013 –Basic research on lung cancer Year: 2013 Effect of 17-oxo-DHA alone and in combination with gemcitabine on lung cancer cell growth Source: International Congress 2016 – Late-breaking translational research in lung cancer Year: 2016 Integrative analysis of DNA copy number in metastatic NSCLC identifies drug sensitivity to Afatinib Source: International Congress 2014 – Pathology and prognostic factors of thoracic tumours Year: 2014 Polymorphism of HLA-G gene promotor in patients with non small cell lung cancer Source: International Congress 2014 – Biology and pathology of thoracic tumours Year: 2014 Proapoptotic effects of PAI-1 protein on lung and prostate cancer cells Source: Annual Congress 2013 –Basic research on lung cancer Year: 2013