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.
authors: Department of Pediatrics, Stanford University, Stanford, California, USA.
authors: Kwon-Sik
authors: KS
authors: Park
authors: Luciano G
authors: LG
authors: Martelotto
authors: Martin
authors: M
authors: Peifer
authors: Martin L
authors: ML
authors: Sos
authors: Anthony N
authors: AN
authors: Karnezis
authors: Moe R
authors: MR
authors: Mahjoub
authors: Katie
authors: K
authors: Bernard
authors: Jamie F
authors: JF
authors: Conklin
authors: Anette
authors: A
authors: Szczepny
authors: Jing
authors: J
authors: Yuan
authors: Ribo
authors: R
authors: Guo
authors: Beatrice
authors: B
authors: Ospina
authors: Jeanette
authors: J
authors: Falzon
authors: Samara
authors: S
authors: Bennett
authors: Tracey J
authors: TJ
authors: Brown
authors: Ana
authors: A
authors: Markovic
authors: Wendy L
authors: WL
authors: Devereux
authors: Cory A
authors: CA
authors: Ocasio
authors: James K
authors: JK
authors: Chen
authors: Tim
authors: T
authors: Stearns
authors: Roman K
authors: RK
authors: Thomas
authors: Marion
authors: M
authors: Dorsch
authors: Silvia
authors: S
authors: Buonamici
authors: D Neil
authors: DN
authors: Watkins
authors: Craig D
authors: CD
authors: Peacock
authors: Julien
authors: J
authors: Sage
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D055752:Small Cell Lung Carcinoma / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53