The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor

• Published in: Molecular cancer therapeutics 2012-03, Vol.11 (3), p.784-791
• Main Authors: Kim, Youngwook, Ko, Jeonghun, Cui, ZhengYun, Abolhoda, Amir, Ahn, Jin Seok, Ou, Sai-Hong, Ahn, Myung-Ju, Park, Keunchil
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adult; Animals; Blotting, Western; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - genetics; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Quinazolines - pharmacology; Quinazolines - therapeutic use; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; RNA Interference; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-11-0750

Molecular target therapies using first-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, have been shown to be effective for patients with non-small cell lung cancer (NSCLC) who harbor activating mutations in EGFR. However, these patients eventually develop resistance to the reversible TKIs, and this has led to the development of second-generation, irreversible EGFR inhibitors. Currently, the mechanism of acquired resistance to irreversible EGFR inhibitors is not clear. Using an in vitro cell culture system, we modeled the acquired resistance to first-line treatment with second-generation EGFR-TKIs using an EGFR-mutant NSCLC cell line. Here, we report a mechanism of resistance involving T790M secondary mutation as well as a corresponding clinical case. The results of these findings suggest that inhibition of EGFR by currently available second-generation EGFR-TKIs may not be sufficient to physiologically prevent the emergence of cells that are still dependent on EGFR signaling. This finding bears important implications on the limitations of currently available second-generation EGFR-TKIs.