@article{becfdc5d99804bfaaa395c864bde64be,
title = "A crucial requirement for Hedgehog signaling in small cell lung cancer",
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.",
author = "Park, {Kwon Sik} and Martelotto, {Luciano G.} and Martin Peifer and Sos, {Martin L.} and Karnezis, {Anthony N.} and Mahjoub, {Moe R.} and Katie Bernard and Conklin, {Jamie F.} and Anette Szczepny and Jing Yuan and Ribo Guo and Beatrice Ospina and Jeanette Falzon and Samara Bennett and Brown, {Tracey J.} and Ana Markovic and Devereux, {Wendy L.} and Ocasio, {Cory A.} and Chen, {James K.} and Tim Stearns and Thomas, {Roman K.} and Marion Dorsch and Silvia Buonamici and Watkins, {D. Neil} and Peacock, {Craig D.} and Julien Sage",
note = "Funding Information: Tobacco-Related Disease Research Program of California (J.F.C.), US National Institutes of Health (NIH) National Cancer Institute R01 CA136574 (J.K.C.), the Flight Attendant Medical Research Institute (YCSA 072033) (C.D.P.), NIH 5T32 CA009302-33 (C.O.), the National Health and Medical Research Council of Australia project grants 546024 and 546098 and the Victorian Cancer Agency (D.N.W., L.G.M. and A.S.), the Deutsche Krebshilfe (107954) (R.K.T.), the German Ministry of Science and Education as part of the Nationales Genomforschungsnetz (NGFN-plus) program (01GS08100) (R.K.T.), the Max Planck Society (MIFA NEUR8061) (R.K.T.), the Deutsche Forschungsgemeinschaft (DFG) through Sonderforschungsbereiche (TP6) (R.K.T.), the Ministry for Innovation, Science, Research and Technology of the State of Nordrhein-Westfalen (MIWT, 4000-12 09) (R.K.T.) and by an anonymous foundation to R.K.T. Funding Information: We would like to thank A. Berns (The Netherlands Cancer Institute) and M. Scott (Stanford University) for the Trp53lox and Ptch1lacZ/+ mice, respectively, J. Whitsett (Cincinnati Children{\textquoteright}s Hospital) for the antibodies to surfactant protein C, C. Janke (Orsay Curie Institute) for antibodies to polyglutamylated tubulin and C.-M. Fan (Carnegie Institution of Washington) for the adenovirally expressed SmoM2 virus, as well as T. Oro, James Kim, Jynho Kim and P. Beachy for helpful discussions throughout the course of this study. We thank R. Toftg{\aa}rd (Karolinska Institute) and K. McGovern at Infinity Pharmaceuticals for their generous gift of the GANT-61 and cyclopamine, respectively, R. Rohatgi for help with the immunoblot analysis and B. Schaffer for help with the cell culture. This work was supported by the Lucile Packard Foundation for Children{\textquoteright}s Health (J.S.), the Damon Runyon Cancer Research Foundation (J.S.), the American Lung Association (J.S. and K.-S.P.), the Francis Family Foundation (K.-S.P.), the American Cancer Society (J.S.), the",
year = "2011",
month = nov,
doi = "10.1038/nm.2473",
language = "English (US)",
volume = "17",
pages = "1504--1508",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "11",
}