{"entity":{"id":"smoothened","kind":"target","name":"Smoothened (hedgehog pathway)","aka":[],"tldr":"The switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.","summary":"Hedgehog ligand binding to PTCH1 releases SMO, a GPCR-like protein, to activate GLI transcription factors. PTCH1 loss (~70%) or SMO mutation (~10-20%) drives essentially all basal cell carcinoma, SHH-subgroup medulloblastoma (~30%) and Gorlin syndrome. Vismodegib (2012) and sonidegib (2015) treat advanced BCC; glasdegib (2018) with low-dose cytarabine treats unfit AML. Class toxicities (muscle spasms, dysgeusia, alopecia, teratogenicity) limit duration; SMO mutations (D473H, W535L) cause resistance; downstream GLI or SUFU-loss tumours do not respond.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Smoothened","links":[{"label":"BCC genomics (Nat Genet 2016)","url":"https://doi.org/10.1038/ng.3525"}],"tags":["gap-fill"],"related":[],"cancers":["basal-cell-carcinoma","medulloblastoma","aml"],"sections":[],"technologies":["kinase-inhibitors"],"targets":[],"drugs":["vismodegib","sonidegib","glasdegib"],"companies":[],"institutions":[],"pathways":["basal-cell-carcinoma-signalling"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-bonilla-nat-genet"],"journals":[],"dependsOn":[],"notes":[],"symbol":"SMO","role":[],"sources":[],"specificity":"broadly-expressed","distribution":"few-types","specificityNote":"Broadly expressed or essential: HPA finds the RNA at low tissue specificity; the 4 medicines aimed at it (Vismodegib, Sonidegib, Glasdegib and more) act on the wild-type protein, so normal tissue is exposed and the therapeutic window comes from the tumour's faster division or its dependence on the protein. HPA SMO: RNA low tissue specificity; no normal tissue stained high; highest cancer staining urothelial cancer (1 of 11 high). Distribution: 3 cancer families in the corpus carry a prevalence row, label threshold or catalogue link for it (Skin cancer (all types), Brain and spinal cord tumours (all types), Leukaemia); Open Targets associates it with 3 specific cancer types at or above 0.5 (basal cell carcinoma, acute myeloid leukemia, medulloblastoma). (Rule 7 of scripts/fetch-target-specificity.ts.)","specificitySources":[{"label":"Human Protein Atlas SMO tissue","url":"https://www.proteinatlas.org/ENSG00000128602-SMO/tissue","note":"RNA tissue and blood lineage specificity, normal tissue antibody staining (version 25.1, CC BY-SA 3.0)"},{"label":"Open Targets ENSG00000128602 associations","url":"https://platform.opentargets.org/target/ENSG00000128602/associations","note":"cancer associations at or above 0.5 (CC0)"}],"hgnc":"HGNC:11119","ensembl":"ENSG00000128602","uniprot":"Q99835","entrez":"6608","firstDescribed":1996,"firstDescribedBasis":"sequence","firstDescribedNote":"Earliest sequence paper UniProt cites for the protein: Stone D.M. et al, Nature, 1996, \"The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog\".","firstDescribedSource":"https://pubmed.ncbi.nlm.nih.gov/8906787/","biology":"Seven-transmembrane Frizzled-class receptor; cholesterol binding to its cysteine-rich domain and transmembrane site activates it once PTCH1 inhibition is relieved, translocating to the primary cilium and derepressing GLI2/3.","whereFound":["Basal cell carcinoma (PTCH1 ~70%, SMO ~10-20%)","SHH medulloblastoma (~30% of medulloblastoma)","Gorlin syndrome (germline PTCH1/SUFU)","AML (pathway activity in leukaemic stem cells)"],"targetClass":"other","prevalence":[{"cancerId":"basal-cell-carcinoma","pct":"85","measure":"hedgehog pathway activation (PTCH1 or SMO)","source":"https://doi.org/10.1038/ng.3525"},{"cancerId":"medulloblastoma","pct":"30","measure":"SHH subgroup"}]},"route":"/targets/smoothened/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"basal-cell-carcinoma","kind":"cancer","name":"Basal cell carcinoma","route":"/cancers/basal-cell-carcinoma/"},{"id":"locally-advanced-bcc","kind":"cancer","name":"Locally advanced and metastatic basal cell carcinoma","route":"/cancers/locally-advanced-bcc/"},{"id":"medulloblastoma","kind":"cancer","name":"Medulloblastoma","route":"/cancers/medulloblastoma/"},{"id":"medulloblastoma-shh","kind":"cancer","name":"SHH-activated medulloblastoma","route":"/cancers/medulloblastoma-shh/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"drug":[{"id":"glasdegib","kind":"drug","name":"Glasdegib","route":"/drugs/glasdegib/"},{"id":"patidegib","kind":"drug","name":"Patidegib","route":"/drugs/patidegib/"},{"id":"sonidegib","kind":"drug","name":"Sonidegib","route":"/drugs/sonidegib/"},{"id":"vismodegib","kind":"drug","name":"Vismodegib","route":"/drugs/vismodegib/"}],"pathway":[{"id":"basal-cell-carcinoma-signalling","kind":"pathway","name":"Basal cell carcinoma (KEGG map)","route":"/pathways/basal-cell-carcinoma-signalling/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"id":"invasion-ecm-degradation","kind":"pathway","name":"Invasion: proteases, adhesion & the invasive front","route":"/pathways/invasion-ecm-degradation/"},{"id":"proteoglycans-in-cancer","kind":"pathway","name":"Proteoglycans in cancer","route":"/pathways/proteoglycans-in-cancer/"}],"paper":[{"id":"paper-bonilla-nat-genet","kind":"paper","name":"Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma","route":"/key-papers/paper-bonilla-nat-genet/"}],"term":[{"id":"hedgehog-inhibitor-tolerability","kind":"term","name":"Why people stop taking hedgehog inhibitors","route":"/terms/hedgehog-inhibitor-tolerability/"}],"trial":[{"id":"bolt","kind":"trial","name":"BOLT","route":"/trials/bolt/"},{"id":"erivance","kind":"trial","name":"ERIVANCE BCC","route":"/trials/erivance/"},{"id":"patidegib-gel-gorlin-phase-2","kind":"trial","name":"Patidegib gel in Gorlin syndrome (phase 2A)","route":"/trials/patidegib-gel-gorlin-phase-2/"},{"id":"stevie","kind":"trial","name":"STEVIE (vismodegib in ordinary practice)","route":"/trials/stevie/"},{"id":"vismoneo","kind":"trial","name":"VISMONEO (vismodegib before surgery for locally advanced basal cell carcinoma)","route":"/trials/vismoneo/"}],"target":[{"id":"ptch1","kind":"target","name":"PTCH1 (Patched 1)","route":"/targets/ptch1/"}]}}