Hedgehog pathway inhibition radiosensitizes non-small cell lung cancers

Jing Zeng, Khaled Aziz, Sivarajan T. Chettiar, Blake T. Aftab, Michael Armour, Rajendra Gajula, Nishant Gandhi, Tarek Salih, Joseph M. Herman, John Wong, Charles M. Rudin, Phuoc T. Tran, Russell K. Hales

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Abstract

Purpose: 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 and Materials: 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 KrasG12D-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.

Original languageEnglish (US)
Pages (from-to)143-149
Number of pages7
JournalInternational Journal of Radiation Oncology Biology Physics
Volume86
Issue number1
DOIs
StatePublished - May 1 2013

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ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Zeng, J., Aziz, K., Chettiar, S. T., Aftab, B. T., Armour, M., Gajula, R., Gandhi, N., Salih, T., Herman, J. M., Wong, J., Rudin, C. M., Tran, P. T., & Hales, R. K. (2013). Hedgehog pathway inhibition radiosensitizes non-small cell lung cancers. International Journal of Radiation Oncology Biology Physics, 86(1), 143-149. https://doi.org/10.1016/j.ijrobp.2012.10.014