A crucial requirement for Hedgehog signaling in small cell lung cancer

• Published in: Nature medicine Vol. 17; no. 11; pp. 1504 - 1508
• Main Authors: Park, Kwon-Sik, Martelotto, Luciano G, Peifer, Martin, Sos, Martin L, Karnezis, Anthony N, Mahjoub, Moe R, Bernard, Katie, Conklin, Jamie F, Szczepny, Anette, Yuan, Jing, Guo, Ribo, Ospina, Beatrice, Falzon, Jeanette, Bennett, Samara, Brown, Tracey J, Markovic, Ana, Devereux, Wendy L, Ocasio, Cory A, Chen, James K, Stearns, Tim, Thomas, Roman K, Dorsch, Marion, Buonamici, Silvia, Watkins, D Neil, Peacock, Craig D, Sage, Julien
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2011; Nature Publishing Group
• Subjects: 631/208/2489/144/68; 631/67/1059; 631/80/86; 692/699/67/1612/2143; Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; Cellular signal transduction; Chemotherapy; Development and progression; Disease Models, Animal; Drug Resistance, Neoplasm; Epithelial Cells - cytology; Epithelial Cells - physiology; Genetic aspects; Genomics; Hedgehog proteins; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Infectious Diseases; letter; Lung - cytology; Lung - metabolism; Lung - pathology; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Metabolic Diseases; Mice; Mice, Knockout; Mice, Nude; Molecular Medicine; Neoplasm Transplantation; Neurosciences; Oncology; Pharmacology; Physiological aspects; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Signal Transduction - physiology; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2473

The authors find that cell-intrinsic activation of Hedgehog signaling without genetic alterations is a contributing feature to the progression and chemotherapy resistance of small-cell lung carcinoma, and that Hedgehog inhibition can prevent lung cancer growth and recurrence. Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment 1 , 2 . Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC 3 , 4 , 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.