Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer

• Published in: Biochemical pharmacology Vol. 80; no. 5; pp. 613 - 623
• Main Authors: Yoshida, Takeshi, Zhang, Guolin, Haura, Eric B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01-09-2010
• Subjects: Acquired resistance; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - pathology; Epidermal growth factor receptor tyrosine kinase inhibitors; Erlotinib; Gefitinib; Gene Amplification; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - pathology; Mutation; Non-small cell lung cancer; Proteomics; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction; Epidermal growth factor receptor tyrosine kinase inhibitors; Acquired resistance; Erlotinib; Gefitinib; Non-small cell lung cancer
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2010.05.014

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Platinum-based doublets remain the current standard therapy for advanced NSCLC. However, overall survival (OS) has reached a plateau, even with the improvement in these regimens. Advances in the knowledge of molecular mechanisms of carcinogenesis have prompted the development of many novel molecular-targeted agents including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results of the recent phase III IPASS trial showed that the EGFR-TKI gefitinib has a superior progression-free survival (PFS) to the most commonly used platinum-based doublet carboplatin-paclitaxel as the first-line chemotherapy for pulmonary lung adenocarcinoma among nonsmokers in East Asia. This trial also demonstrated that the presence of
EGFR mutation is the best predictor of gefitinib treatment compared with the other biomarkers including
EGFR gene copy number. Despite the therapeutic benefit of EGFR-TKIs in NSCLC, most patients eventually develop resistance to these drugs. A secondary mutation of
EGFR (T790M) and amplification of
MET account for 70% of all cases of acquired resistance to EGFR-TKIs. This review summarizes the significance of
EGFR mutations and the mechanisms of resistance to EGFR-TKIs in NSCLC, both of which are critical for patient selection to extend survival as well as to overcome resistance in NSCLC patients treated with EGFR-TKIs.