Loss of PTEN Expression by Blocking Nuclear Translocation of EGR1 in Gefitinib-Resistant Lung Cancer Cells Harboring Epidermal Growth Factor Receptor―Activating Mutations

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 21; pp. 8715 - 8725
• Main Authors: YAMAMOTO, Chizuko, BASAKI, Yuji, ONO, Mayumi, KAWAHARA, Akihiko, NAKASHIMA, Kazutaka, KAGE, Masayoshi, IZUMI, Hiroto, KOHNO, Kimitoshi, URAMOTO, Hidetaka, YASUMOTO, Kosei, KUWANO, Michihiko
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.11.2010
• Subjects: Antineoplastic agents; Biological and medical sciences; Blotting, Western; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cell Proliferation - drug effects; Chromosome aberrations; Drug Resistance, Neoplasm; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Erlotinib Hydrochloride; Humans; Immunoenzyme Techniques; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical genetics; Medical sciences; Mutation - genetics; Pharmacology. Drug treatments; Phosphorylation - drug effects; Pneumology; Protein Kinase Inhibitors - therapeutic use; Protein Transport - drug effects; PTEN Phosphohydrolase - antagonists & inhibitors; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Quinazolines - therapeutic use; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - pharmacology; Tumor Cells, Cultured; Tumors; Tumors of the respiratory system and mediastinum; Chromosomal aberration; Antineoplastic agent; Cell proliferation; Quinazoline derivatives; Lung cancer; Bronchopulmonary; Epidermal growth factor receptor; Bronchus disease; Genetics; PTEN Gene; Gefitinib; Protein-tyrosine kinase; Tumor cell; Tumor suppressor gene; Chromosome translocation; Lung disease; Early Growth Response Transcription Factor 1; Enzyme; Tyrosine kinase inhibitor; Respiratory disease; Transferases; Enzyme inhibitor; Malignant tumor; Gene expression; Resistance; Growth factor receptor; Cytogenetics; Abnormal chromosome; Mutation; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-10-0043

Gefitinib (Iressa) and erlotinib (Tarceva), which target the epidermal growth factor receptor (EGFR), are approved for treatment of patients with advanced non-small cell lung cancer (NSCLC). Patients whose tumors harbor mutations in the EGFR gene, including delE746-A750 in exon 19 and L858R in exon 21, may benefit in particular from gefitinib treatment. However, acquired resistance to gefitinib has been a serious clinical problem, and further optimization is needed for application of EGFR-targeted drugs in lung cancer patients. In this study, we established gefitinib-resistant NSCLC cells from PC-9 cell line, which harbors the delE746-A750 mutation, by exposing the cell line to gefitinib for over 7 months. Gefitinib-resistant PC-9/GEFs cell lines showed a marked downregulation of PTEN expression and increased Akt phosphorylation. In revertant, gefitinib-sensitive clones (PC-9/Rev) derived from PC-9/GEF1-1 and PC-9/GEF2-1, PTEN expression, as well as sensitivity to gefitinib and erlotinib, was restored. Knockdown of PTEN expression using small interfering RNA specific for PTEN in PC-9 cells resulted in drug resistance to gefitinib and erlotinib. Nuclear translocation of the EGR1 transcription factor, which regulates PTEN expression, was shown to be suppressed in resistant clones and restored in their revertant clones. Reduced PTEN expression was also seen in tumor samples from a patient with gefitinib-refractory NSCLC. This study thus strongly suggests that loss of PTEN expression contributes to gefitinib and erlotinib resistance in NSCLC. Our findings reinforce the therapeutic importance of PTEN expression in the treatment of NSCLC with EGFR-targeted drugs.