title: Hsp90 inhibition overcomes HGF-triggering resistance to EGFR-TKIs in EGFR-mutant lung cancer by decreasing client protein expression and angiogenesis.
abstract: BACKGROUND
  The three major clinically relevant mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant lung cancer are a second mutation in the EGFR gene (T790M), Met amplification, and increased expression of hepatocyte growth factor (HGF). Heat shock protein90 (Hsp90) is a 90 kDa molecular chaperone for proteins that include EGFR, Met, and echinoderm microtubule-associated proetin-like-4-the anaplastic lymphoma kinase. Here, we determined whether inhibition of Hsp90 could overcome HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer cells.
  
  
  METHODS
  The effects of the Hsp90 inhibitor 17-demethoxygeldanamycin (17-DMAG) on the growth of lung cancer cells resistant to the EGFR-TKI were examined in the presence and absence of HGF, and in cells transfected with the HGF gene in vitro and in vivo.
  
  
  RESULTS
  EGFR-TKI erlotinib did not inhibit the growth of HGF-gene transfected Ma-1 (Ma-1/HGF) cells and H1975 cells, containing the EGFR L858R and T790M mutations, respectively. Erlotinib also did not inhibit the growth of PC-9 and Ma-1 cells, with deletions in EGFR exon19, in the presence of HGF. However, 17-DMAG induced apoptosis and markedly inhibited the growth of these cell lines, even in the presence of HGF. This inhibition by 17-DMAG was associated with decreased expression of EGFR and Met in tumor cells. An in vivo model of HGF-triggered erlotinib-resistance, which used Ma-1/HGF cells, showed that 17-DMAG markedly suppressed tumor growth by decreasing angiogenesis and increasing apoptosis.
  
  
  CONCLUSIONS
  Hsp90 inhibitors may overcome HGF-triggered resistance to EGFR-TKIs and may result in more successful treatment of patients with EGFR-mutant lung cancers.
authors.affiliation: Division of Medical Oncology, †Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Koizumi
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Kita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Kenichi
authors.initials: K
authors.lastname: Suda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D014443:Tyrosine; D017228:Hepatocyte Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors