title: Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations.
abstract: Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan. syano@staff.kanazawa-u.ac.jp
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Haruko
authors.initials: H
authors.lastname: Sakurama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ogino
authors.forename: Soji
authors.initials: S
authors.lastname: Kakiuchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Hanibuchi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Saburo
authors.initials: S
authors.lastname: Sone
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077156:Gefitinib; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines / Q000494:pharmacology*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020893:Receptor, ErbB-3; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib