Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations

Hedgehog (HH) pathway Smoothened (Smo) inhibitors are active against Gorlinsyndrome-associated basal cell carcinoma (BCC) and medulloblastoma where Patched(Ptch) mutations occur. We interrogated 705 epithelial cancer cell lines for growthresponse to the Smo inhibitor cyclopamine and for expressed HH pathway-regulatedspecies in a linked genetic database. Ptch and Smo mutations that respectivelyconferred Smo inhibitor response or resistance were undetected. Previous studiesrevealed HH pathway activation in lung cancers. Therefore, findings were validatedusing lung cancer cell lines, transgenic and transplantable murine lung cancermodels, and human normal-malignant lung tissue arrays in addition to testing otherSmo inhibitors. Cyclopamine sensitivity most significantly correlated with highcyclin E (P=0.9) and low insulin-like growth factor binding protein 6 (IGFBP6)(P=0.4) levels. Gli family members were associated with response. Cyclopamineresistance occurred with high GILZ (P=0.002) expression. Newer Smo inhibitorsexhibited a pattern of sensitivity similar to cyclopamine. Gain of cyclin E orloss of IGFBP6 in lung cancer cells significantly increased Smo inhibitor response.Cyclin E-driven transgenic lung cancers expressed a gene profile implicating HHpathway activation. Cyclopamine treatment significantly reduced proliferationof murine and human lung cancers. Smo inhibition reduced lung cancer formationin a syngeneic mouse model. In human normal-malignant lung tissue arrays cyclinE, IGFBP6, Gli1 and GILZ were each differentially expressed. Together, these findingsindicate that Smo inhibitors should be considered in cancers beyond those withactivating HH pathway mutations. This includes tumors that express genes indicatingbasal HH pathway activation.