A crucial requirement for Hedgehog signaling in small cell lung cancer

Kwon Sik Park, Luciano G. Martelotto, Martin Peifer, Martin L. Sos, Anthony Karnezis, Moe R. Mahjoub, Katie Bernard, Jamie F. Conklin, Anette Szczepny, Jing Yuan, Ribo Guo, Beatrice Ospina, Jeanette Falzon, Samara Bennett, Tracey J. Brown, Ana Markovic, Wendy L. Devereux, Cory A. Ocasio, James K. Chen, Tim StearnsRoman K. Thomas, Marion Dorsch, Silvia Buonamici, D. Neil Watkins, Craig D. Peacock, Julien Sage

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160 Scopus citations

Abstract

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment. Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC, we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo. Reciprocally, deletion of Smo in Rb1 and Trp53-mutant lung epithelial cells strongly suppressed SCLC initiation and progression in mice. Furthermore, pharmacological blockade of Hedgehog signaling inhibited the growth of mouse and human SCLC, most notably following chemotherapy. These findings show a crucial cell-intrinsic role for Hedgehog signaling in the development and maintenance of SCLC and identify Hedgehog pathway inhibition as a therapeutic strategy to slow the progression of disease and delay cancer recurrence in individuals with SCLC.

Original languageEnglish (US)
Pages (from-to)1504-1508
Number of pages5
JournalNature Medicine
Volume17
Issue number11
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Park, K. S., Martelotto, L. G., Peifer, M., Sos, M. L., Karnezis, A., Mahjoub, M. R., Bernard, K., Conklin, J. F., Szczepny, A., Yuan, J., Guo, R., Ospina, B., Falzon, J., Bennett, S., Brown, T. J., Markovic, A., Devereux, W. L., Ocasio, C. A., Chen, J. K., ... Sage, J. (2011). A crucial requirement for Hedgehog signaling in small cell lung cancer. Nature Medicine, 17(11), 1504-1508. https://doi.org/10.1038/nm.2473