title: Response to inhibition of smoothened in diverse epithelial cancer cells             that lack smoothened or patched 1 mutations.
abstract: Hedgehog (HH) pathway Smoothened (Smo) inhibitors are active against Gorlin             syndrome-associated basal cell carcinoma (BCC) and medulloblastoma where Patched             (Ptch) mutations occur. We interrogated 705 epithelial cancer cell lines for growth             response to the Smo inhibitor cyclopamine and for expressed HH pathway-regulated             species in a linked genetic database. Ptch and Smo mutations that respectively             conferred Smo inhibitor response or resistance were undetected. Previous studies             revealed HH pathway activation in lung cancers. Therefore, findings were validated             using lung cancer cell lines, transgenic and transplantable murine lung cancer             models, and human normal-malignant lung tissue arrays in addition to testing other             Smo inhibitors. Cyclopamine sensitivity most significantly correlated with high             cyclin E (P=0.000009) and low insulin-like growth factor binding protein 6 (IGFBP6)             (P=0.000004) levels. Gli family members were associated with response. Cyclopamine             resistance occurred with high GILZ (P=0.002) expression. Newer Smo inhibitors             exhibited a pattern of sensitivity similar to cyclopamine. Gain of cyclin E or             loss of IGFBP6 in lung cancer cells significantly increased Smo inhibitor response.             Cyclin E-driven transgenic lung cancers expressed a gene profile implicating HH             pathway activation. Cyclopamine treatment significantly reduced proliferation             of murine and human lung cancers. Smo inhibition reduced lung cancer formation             in a syngeneic mouse model. In human normal-malignant lung tissue arrays cyclin             E, IGFBP6, Gli1 and GILZ were each differentially expressed. Together, these findings             indicate that Smo inhibitors should be considered in cancers beyond those with             activating HH pathway mutations. This includes tumors that express genes indicating             basal HH pathway activation.
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine                     at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Galimberti
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Busch
authors.forename: Fadzai
authors.initials: F
authors.lastname: Chinyengetere
authors.forename: Tian
authors.initials: T
authors.lastname: Ma
authors.forename: David
authors.initials: D
authors.lastname: Sekula
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Memoli
authors.forename: Konstantin H
authors.initials: KH
authors.lastname: Dragnev
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Johnson
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guo
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Freemantle
authors.forename: Angeline S
authors.initials: AS
authors.lastname: Andrew
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
authors.forename: Cyril
authors.initials: C
authors.lastname: Benes
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins; D006801:Humans; D051379:Mice; D009154:Mutation; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D019927:Cyclin E; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; C000541:cyclopamine