title: Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer.
abstract: KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors.
  
  
  
  Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non-small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754-69. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan. First Department of Medicine, Hokkaido University School of Medicine, Hokkaido, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kitai
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan. Institute for Frontier Science Initiative, Kanazawa University, Ishikawa, Japan. hebi@staff.kanazawa-u.ac.jp syano@staff.kanazawa-u.ac.jp.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.affiliation: Department of Biobank, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.affiliation: VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Konstantinos V
authors.initials: KV
authors.lastname: Floros
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kotani
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Hokkaido, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Oizumi
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Hokkaido, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Ishikawa, Japan. hebi@staff.kanazawa-u.ac.jp syano@staff.kanazawa-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C106534:FRS2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; C499038:SPRY4 protein, human; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins