Hedgehog pathway inhibition radiosensitizes non-small cell lung cancers. Academic Article uri icon

Overview

MeSH

  • Adenocarcinoma
  • Anilides
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Pyridines
  • Transplantation, Heterologous

MeSH Major

  • Carcinoma, Non-Small-Cell Lung
  • Hedgehog Proteins
  • Lung Neoplasms
  • Neoplasm Proteins
  • Radiation Tolerance

abstract

  • 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. 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. 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. 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. Copyright © 2013 Elsevier Inc. All rights reserved.

publication date

  • May 1, 2013

has subject area

  • Adenocarcinoma
  • Anilides
  • Animals
  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung
  • Cell Line, Tumor
  • Cell Survival
  • Female
  • Hedgehog Proteins
  • Humans
  • Lung Neoplasms
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasm Proteins
  • Pyridines
  • Radiation Tolerance
  • Transplantation, Heterologous

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4145860

Digital Object Identifier (DOI)

  • 10.1016/j.ijrobp.2012.10.014

PubMed ID

  • 23182391

Additional Document Info

start page

  • 143

end page

  • 149

volume

  • 86

number

  • 1