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The Hedgehog processing pathway is required for NSCLC growth and survival

Oncogene volume 32, pages 2335–2345 (2013)Cite this article

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Abstract

Considerable interest has been generated from the results of recent clinical trials using smoothened (SMO) antagonists to inhibit the growth of hedgehog (HH) signaling-dependent tumors. This interest is tempered by the discovery of SMO mutations mediating resistance, underscoring the rationale for developing therapeutic strategies that interrupt HH signaling at levels distinct from those inhibiting SMO function. Here, we demonstrate that HH-dependent non-small cell lung carcinoma (NSCLC) growth is sensitive to blockade of the HH pathway upstream of SMO, at the level of HH ligand processing. Individually, the use of different lentivirally delivered shRNA constructs targeting two functionally distinct HH-processing proteins, skinny hedgehog (SKN) or dispatched-1 (DISP-1), in NSCLC cell lines produced similar decreases in cell proliferation and increased cell death. Further, providing either an exogenous source of processed HH or a SMO agonist reverses these effects. The attenuation of HH processing, by knocking down either of these gene products, also abrogated tumor growth in mouse xenografts. Finally, we extended these findings to primary clinical specimens, showing that SKN is frequently overexpressed in NSCLC and that higher DISP-1 expression is associated with an unfavorable clinical outcome. Our results show a critical role for HH processing in HH-dependent tumors, identifies two potential druggable targets in the HH pathway, and suggest that similar therapeutic strategies could be explored to treat patients harboring HH ligand-dependent cancers.

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Acknowledgements

This work was supported by the NIH grants GM64011 (DJ Robbins), R03-CA132166 (E Dmitrovsky), R01-CA087546 (E Dmitrovsky) and R01-CA111422 (E Dmitrovsky); grants from the Samuel Waxman Cancer Research Foundation (E Dmitrovsky, A Capobianco); FICYT-POST10-27 (J Rodriguez-Blanco) and from the American Lung Association/LUNGevity Foundation (DJ Robbins). E Dmitrovsky is an American Cancer Society Professor supported by a generous gift from the FM Kirby Foundation.

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  1. J Rodriguez-Blanco and N S Schilling: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Molecular Oncology Program, University of Miami, Miami, FL, USA

    J Rodriguez-Blanco, N S Schilling, R Tokhunts, C Giambelli, J Long, D Liang Fei, S Singh, K E Black, Z Wang, D M Nguyen, A J Capobianco & D J Robbins

  2. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA

    N S Schilling, R Tokhunts, D Liang Fei, F Galimberti & E Dmitrovsky

  3. Department of Pathology, University of Miami, Miami, FL, USA

    P A Bejarano

  4. Department of Surgery, Laboratory on Sex and Gender Differences in Health and Disease, University of Miami, Miami, FL, USA

    S Elliot

  5. Department of Medicine and Department of Surgery, Pulmonary and Critical Care Medicine, Jackson Memorial Hospital, University of Miami, Miami, FL, USA

    M K Glassberg

  6. Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA

    D M Nguyen, A J Capobianco & D J Robbins

  7. Cancer Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA

    W W Lockwood

  8. Department of Integrative Biology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada

    W L Lam

  9. Norris Cotton Cancer Center, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    E Dmitrovsky

  10. Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL, USA

    D J Robbins

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  1. J Rodriguez-Blanco
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Rodriguez-Blanco, J., Schilling, N., Tokhunts, R. et al. The Hedgehog processing pathway is required for NSCLC growth and survival. Oncogene 32, 2335–2345 (2013). https://doi.org/10.1038/onc.2012.243

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