title: mTOR inhibitors control the growth of EGFR mutant lung cancer even after acquiring resistance by HGF.
abstract: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, is a critical problem in the treatment of EGFR mutant lung cancer. Several mechanisms, including bypass signaling by hepatocyte growth factor (HGF)-triggered Met activation, are implicated as mediators of resistance. The mammalian target of rapamycin (mTOR), is a downstream conduit of EGFR and MET signaling, and is thus considered a therapeutically attractive target in the treatment of various types of cancers. The purpose of this study was to examine whether 2 clinically approved mTOR inhibitors, temsirolimus and everolimus, overcome HGF-dependent resistance to EGFR-TKIs in EGFR mutant lung cancer cells. Both temsirolimus and everolimus inhibited the phosphorylation of p70S6K and 4E-BP1, which are downstream targets of the mTOR pathway, and reduced the viability of EGFR mutant lung cancer cells, PC-9, and HCC827, even in the presence of HGF in vitro. In a xenograft model, temsirolimus suppressed the growth of PC-9 cells overexpressing the HGF-gene; this was associated with suppression of the mTOR signaling pathway and tumor angiogenesis. In contrast, erlotinib did not suppress this signaling pathway or tumor growth. Multiple mechanisms, including the inhibition of vascular endothelial growth factor production by tumor cells and suppression of endothelial cell viability, contribute to the anti-angiogenic effect of temsirolimus. These findings indicate that mTOR inhibitors may be useful for controlling HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer, and they provide the rationale for clinical trials of mTOR inhibitors in patients stratified by EGFR mutation and HGF expression status.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishikawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Takako
authors.initials: T
authors.lastname: Sano
authors.forename: Junya
authors.initials: J
authors.lastname: Nakade
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nanjo
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Lu
authors.initials: L
authors.lastname: Zhao
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yasumoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kagamu
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yoshizawa
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000235:genetics*; D000068338:Everolimus; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D017228:Hepatocyte Growth Factor; D000068338:Everolimus; C512478:EGFR protein, human; D066246:ErbB Receptors; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus