@article{oai:kanazawa-u.repo.nii.ac.jp:00013745,
 author = {矢野, 聖二},
 journal = {肺癌 = Japanese journal of Lung Cancer},
 month = {Dec},
 note = {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. EGFR活性型変異を有する肺腺癌はEGFRチロシンキナーゼ阻害薬であるゲフィチニブやエルロチニブが著効する．しかし，EGFR活性型変異を有する肺腺癌の25∼30%はゲフィチニブに自然耐性を示す．また，奏効症例においてもその大半が1年程度で獲得耐性を生じ再燃するため，EGFR活性型変異を有する肺腺癌におけるゲフィチニブ耐性の克服は臨床的にも重要な検討課題である．EGFRのT790M second mutationやMET増幅が,獲得耐性のそれぞれ50%および20%に関与することが知られているが，残りの30%の症例の耐性機序および自然耐性の機序は不明である．著者らは，肝細胞増殖因子（HGF）による第三の耐性機序を明らかにした．癌細胞自身あるいは間質の線維芽細胞が産生するHGFは，その受容体であるMETをリン酸化し，EGFRやErbB3とは無関係にPI3K/Akt経路を活性化することにより，ゲフィチニブ耐性を誘導した．HGF-MET阻害薬はHGFによるEGFR-TKI耐性を克服することも見出した．以上より，HGF-MET経路はEGFR-TKIの治療効果をより高める上で，非常に重要な標的と考えられる．},
 pages = {939--943},
 title = {EGFR-TKIの耐性機序},
 volume = {49},
 year = {2009}
}