title: Hedgehog pathway inhibition radiosensitizes non-small cell lung cancers.
abstract: OBJECTIVE
  Despite improvements in chemoradiation, local control remains a major clinical problem in locally advanced non-small cell lung cancer. The Hedgehog pathway has been implicated in tumor recurrence by promoting survival of tumorigenic precursors and through effects on tumor-associated stroma. Whether Hedgehog inhibition can affect radiation efficacy in vivo has not been reported.
  
  
  METHODS
  We evaluated the effects of a targeted Hedgehog inhibitor (HhAntag) and radiation on clonogenic survival of human non-small cell lung cancer lines in vitro. Using an A549 cell line xenograft model, we examined tumor growth, proliferation, apoptosis, and gene expression changes after concomitant HhAntag and radiation. In a transgenic mouse model of Kras(G12D)-induced and Twist1-induced lung adenocarcinoma, we assessed tumor response to radiation and HhAntag by serial micro-computed tomography (CT) scanning.
  
  
  RESULTS
  In 4 human lung cancer lines in vitro, HhAntag showed little or no effect on radiosensitivity. By contrast, in both the human tumor xenograft and murine inducible transgenic models, HhAntag enhanced radiation efficacy and delayed tumor growth. By use of the human xenograft model to differentiate tumor and stromal effects, mouse stromal cells, but not human tumor cells, showed significant and consistent downregulation of Hedgehog pathway gene expression. This was associated with increased tumor cell apoptosis.
  
  
  CONCLUSIONS
  Targeted Hedgehog pathway inhibition can increase in vivo radiation efficacy in lung cancer preclinical models. This effect is associated with pathway suppression in tumor-associated stroma. These data support clinical testing of Hedgehog inhibitors as a component of multimodality therapy for locally advanced non-small cell lung cancer.
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-2410, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zeng
authors.forename: Khaled
authors.initials: K
authors.lastname: Aziz
authors.forename: Sivarajan T
authors.initials: ST
authors.lastname: Chettiar
authors.forename: Blake T
authors.initials: BT
authors.lastname: Aftab
authors.forename: Michael
authors.initials: M
authors.lastname: Armour
authors.forename: Rajendra
authors.initials: R
authors.lastname: Gajula
authors.forename: Nishant
authors.initials: N
authors.lastname: Gandhi
authors.forename: Tarek
authors.initials: T
authors.lastname: Salih
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Herman
authors.forename: John
authors.initials: J
authors.lastname: Wong
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Phuoc T
authors.initials: PT
authors.lastname: Tran
authors.forename: Russell K
authors.initials: RK
authors.lastname: Hales
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D000813:Anilides; D053823:Hedgehog Proteins; C538724:HhAntag691; D009363:Neoplasm Proteins; D011725:Pyridines