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Vol.49 No.6 contents | Japanese/English |
 | Full Text of PDF (411K) Article in Japanese |
- The 23rd Lung Cancer Workshop -
Molecular Mechanism of EGFR-TKI Resistance
Seiji Yano1,21Kanazawa University Hospital Cancer Center, Japan, 2Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Japan
Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations (EGFRmu) responds favorably to the EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib. However, 25-30% of patients with EGFRmu show intrinsic resistance, and even responders invariably acquire resistance to EGFR-TKIs. Two mechanisms, second-site T790M point mutation in EGFR and MET amplification, which contribute to acquired resistance to EGFR-TKIs have been reported. T790M secondary mutation and MET amplification are found in approximately 50% and 20%, respectively, of patients acquiring resistance to EGFR-TKIs. However, the mechanisms of intrinsic resistance and the other 30% of cases of acquired resistance are still unknown. We recently reported hepatocyte growth factor (HGF) induced resistance as the third mechanism of EGFR-TKI resistance. HGF, produced by either cancer cells or host fibroblasts, induced resistance by restoring PI3K/Akt pathway via MET, independently of ErbB3. In addition, inhibitors of HGF-MET successfully overcame HGF-induced resistance to EGFR-TKIs, indicating the importance of HGF-MET signaling as a considerable target for more successful treatment with EGFR-TKIs.
key words: HGF, MET, EGFR-TKI, Drug resistance, Molecular targeted drugs
JJLC 49 (6): 939-943, 2009
