title: Combined MEK and VEGFR inhibition in orthotopic human lung cancer models results in enhanced inhibition of tumor angiogenesis, growth, and metastasis.
abstract: OBJECTIVE
  Ras/Raf/mitogen-activated protein-extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK signaling is critical for tumor cell proliferation and survival. Selumetinib is a potent, selective, and orally available MEK1/2 inhibitor. In this study, we evaluated the therapeutic efficacy of selumetinib alone or with cediranib, an orally available potent inhibitor of all three VEGF receptor (VEGFR) tyrosine kinases, in murine orthotopic non-small cell lung carcinoma (NSCLC) models.
  
  
  METHODS
  NCI-H441 or NCI-H460 KRAS-mutant human NSCLC cells were injected into the lungs of mice. Mice were randomly assigned to treatment with selumetinib, cediranib, paclitaxel, selumetinib plus cediranib, or control. When controls became moribund, all animals were sacrificed and assessed for lung tumor burden and locoregional metastasis. Lung tumors and adjacent normal tissues were subjected to immunohistochemical analyses.
  
  
  RESULTS
  Selumetinib inhibited lung tumor growth and, particularly at higher dose, reduced locoregional metastasis, as did cediranib. Combining selumetinib and cediranib markedly enhanced their antitumor effects, with near complete suppression of metastasis. Immunohistochemistry of tumor tissues revealed that selumetinib alone or with cediranib reduced ERK phosphorylation, angiogenesis, and tumor cell proliferation and increased apoptosis. The antiangiogenic and apoptotic effects were substantially enhanced when the agents were combined. Selumetinib also inhibited lung tumor VEGF production and VEGFR signaling.
  
  
  CONCLUSIONS
  In this study, we evaluated therapy directed against MEK combined with antiangiogenic therapy in distinct orthotopic NSCLC models. MEK inhibition resulted in potent antiangiogenic effects with decreased VEGF expression and signaling. Combining selumetinib with cediranib enhanced their antitumor and antiangiogenic effects. We conclude that combining selumetinib and cediranib represents a promising strategy for the treatment of NSCLC.
authors.affiliation: Department of Radiation Oncology The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takahashi
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komaki
authors.forename: Paul D
authors.initials: PD
authors.lastname: Smith
authors.forename: Juliane M
authors.initials: JM
authors.lastname: Jürgensmeier
authors.forename: Anderson
authors.initials: A
authors.lastname: Ryan
authors.forename: B Nebiyou
authors.initials: BN
authors.lastname: Bekele
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Jacoby
authors.forename: Maria V
authors.initials: MV
authors.lastname: Korshunova
authors.forename: Anna
authors.initials: A
authors.lastname: Biernacka
authors.forename: Baruch
authors.initials: B
authors.lastname: Erez
authors.forename: Keiko
authors.initials: K
authors.lastname: Hosho
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.forename: Michael S
authors.initials: MS
authors.lastname: O'Reilly
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage* / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D001562:Benzimidazoles; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; D018631:ras Proteins; C517975:AZD 6244; C117307:KRAS protein, human; C500926:cediranib; D007211:Indoles