Mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitor in Korean patients with lung cancer
Open Access
- 27 December 2013
- journal article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 13 (1), 1-8
- https://doi.org/10.1186/1471-2407-13-606
Abstract
Background: Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations. Methods: Among patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry. Results: Twenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%) and four of these patients had other co-existing resistance mechanisms; increased AXL expression was observed in 5/26 patients (19.2%), MET gene amplification was noted in 3/26 (11.5%), and one patient acquired a mutation in the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) gene. None of the patients exhibited EMT; however, increased CD56 expression suggesting neuroendocrine differentiation was observed in two patients. Interestingly, conversion from L858R-mutant to wild-type EGFR occurred in one patient. Seven patients (26.9%) did not exhibit any known resistance mechanisms. Patients with a T790M mutation showed a more favorable prognosis. Conclusion: The mechanisms and frequency of acquired EGFR-TKI resistance in Koreans are comparable to those observed in Western populations; however, more data regarding the mechanisms that drive EGFR-TKI resistance are necessary.Keywords
This publication has 25 references indexed in Scilit:
- Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancerNature Genetics, 2012
- Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR InhibitorsScience Translational Medicine, 2011
- Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008International Journal of Cancer, 2010
- Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung CancerJournal of Clinical Oncology, 2010
- Screening for Epidermal Growth Factor Receptor Mutations in Lung CancerNew England Journal of Medicine, 2009
- Gefitinib or Carboplatin–Paclitaxel in Pulmonary AdenocarcinomaNew England Journal of Medicine, 2009
- MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinibProceedings of the National Academy of Sciences of the United States of America, 2007
- MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 SignalingScience, 2007
- EGFRMutation and Resistance of Non–Small-Cell Lung Cancer to GefitinibNew England Journal of Medicine, 2005
- Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase DomainPLoS Medicine, 2005