Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma - PubMed (original) (raw)
Expression of selected gene for acquired drug resistance to EGFR-TKI in lung adenocarcinoma
Hidetaka Uramoto et al. Lung Cancer. 2011 Sep.
Abstract
Background: Individualized treatment is an attractive challenge that may allow for more effective and safer treatment of human disease. Activating mutations in the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma are associated with a dramatic clinical response to EGFR-tyrosine kinase inhibitors (TKIs). However, patients often experience a relapse after treatment with EGFR-TKIs, even when the tumors are initially highly sensitive. However, the "whole picture" regarding acquired resistance remains unclear.
Methods: Tumor specimens were collected from 11 lung adenocarcinoma patients before and after treatment with gefitinib. The status of the EGFR and K-ras genes were investigated by PCR-based analyses. Immunohistochemistry and real-time PCR assays were used to evaluate the MET gene in terms of its tyrosine phosphorylation and amplification, respectively. The expression of HGF, PTEN, and EGR-1, and changes in the epithelial-mesenchymal transition (EMT) status including the expression of E-cadherin and gamma-catenin as epithelial markers, and vimentin and fibronectin as mesenchymal markers, were evaluated by immunohistochemistry.
Results: Seven (64%) of the gefitinib refractory tumors exhibited a secondary threonine-to-methionine mutation at codon 790 in EGFR (T790M). All of the tumors had wild type K-ras gene expression. No MET amplification was detected in any of the samples, nor was there phosphorylation of MET detected in any of the resistant samples. Neither MET gene amplification, nor the overexpression of HGF was observed in samples without the T790M mutation. A strong expression of HGF was detected in 6 of 8 specimens with the T790M mutation. Three (38%) of 8 cases showed a loss of PTEN in samples with the T790M mutation. A loss of EGR-1 was detected in 2 (29%) of 7 cases, including one tumor without PTEN. Four (57%) of 7 cases showed positive expression of phosphorylated Akt (p-Akt). A change in the EMT status between pre-and post-treatment was observed in 4 (44%) of 9 cases. In all examined samples cases, some alterations of gene or proteins were observed.
Conclusions: The current results showed that these alterations in gene or protein expression can account for all resistant mechanisms. This phenomenon suggests the existence of complicated relationships among acquired resistance-related genes.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Similar articles
- Prognostic value of acquired resistance-related molecules in Japanese patients with NSCLC treated with an EGFR-TKI.
Uramoto H, Yamada T, Yano S, Kondo N, Hasegawa S, Tanaka F. Uramoto H, et al. Anticancer Res. 2012 Sep;32(9):3785-90. Anticancer Res. 2012. PMID: 22993320 - Comprehensive molecular analyses of lung adenocarcinoma with regard to the epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status.
Onitsuka T, Uramoto H, Ono K, Takenoyama M, Hanagiri T, Oyama T, Izumi H, Kohno K, Yasumoto K. Onitsuka T, et al. J Thorac Oncol. 2010 May;5(5):591-6. doi: 10.1097/JTO.0b013e3181d0a4db. J Thorac Oncol. 2010. PMID: 20150826 - Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma.
Uramoto H, Iwata T, Onitsuka T, Shimokawa H, Hanagiri T, Oyama T. Uramoto H, et al. Anticancer Res. 2010 Jul;30(7):2513-7. Anticancer Res. 2010. PMID: 20682976 - Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.
Suda K, Mizuuchi H, Maehara Y, Mitsudomi T. Suda K, et al. Cancer Metastasis Rev. 2012 Dec;31(3-4):807-14. doi: 10.1007/s10555-012-9391-7. Cancer Metastasis Rev. 2012. PMID: 22736441 Review. - Acquired resistance of non-small cell lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors.
Nurwidya F, Takahashi F, Murakami A, Kobayashi I, Kato M, Shukuya T, Tajima K, Shimada N, Takahashi K. Nurwidya F, et al. Respir Investig. 2014 Mar;52(2):82-91. doi: 10.1016/j.resinv.2013.07.007. Epub 2013 Aug 30. Respir Investig. 2014. PMID: 24636263 Review.
Cited by
- RPF2 mediates the CARM1‑MYCN axis to promote chemotherapy resistance in colorectal cancer cells.
Lu M, Hu X, Cheng C, Zhang Y, Huang L, Kong X, Li Z, Zhang Q, Zhang Y. Lu M, et al. Oncol Rep. 2024 Jan;51(1):11. doi: 10.3892/or.2023.8670. Epub 2023 Nov 24. Oncol Rep. 2024. PMID: 37997821 Free PMC article. - Osimertinib resistance prognostic gene signature: STRIP2 is associated with immune infiltration and tumor progression in lung adenocarcinoma.
Zhang G, Guan H, Ning YL, Yao K, Tang H, Muhetaer G, Li H, Zhou J. Zhang G, et al. J Cancer Res Clin Oncol. 2023 Nov;149(17):15573-15588. doi: 10.1007/s00432-023-05294-w. Epub 2023 Aug 31. J Cancer Res Clin Oncol. 2023. PMID: 37648810 - The potential of ferroptosis combined with radiotherapy in cancer treatment.
Lu Z, Xiao B, Chen W, Tang T, Zhuo Q, Chen X. Lu Z, et al. Front Oncol. 2023 Mar 17;13:1085581. doi: 10.3389/fonc.2023.1085581. eCollection 2023. Front Oncol. 2023. PMID: 37007068 Free PMC article. Review. - Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies.
Shi ZD, Pang K, Wu ZX, Dong Y, Hao L, Qin JX, Wang W, Chen ZS, Han CH. Shi ZD, et al. Signal Transduct Target Ther. 2023 Mar 11;8(1):113. doi: 10.1038/s41392-023-01383-x. Signal Transduct Target Ther. 2023. PMID: 36906600 Free PMC article. Review. - Features of tumor-microenvironment images predict targeted therapy survival benefit in patients with EGFR-mutant lung cancer.
Wang S, Rong R, Yang DM, Fujimoto J, Bishop JA, Yan S, Cai L, Behrens C, Berry LD, Wilhelm C, Aisner D, Sholl L, Johnson BE, Kwiatkowski DJ, Wistuba II, Bunn PA Jr, Minna J, Xiao G, Kris MG, Xie Y. Wang S, et al. J Clin Invest. 2023 Jan 17;133(2):e160330. doi: 10.1172/JCI160330. J Clin Invest. 2023. PMID: 36647832 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Research Materials
Miscellaneous