{"entity":{"id":"hedgehog","kind":"pathway","name":"Hedgehog signalling","aka":[],"tldr":"A developmental pathway that shapes embryos and is switched back on in basal cell skin cancer and some brain tumours. Blocking it cures most advanced basal cell carcinomas, but tumours learn to reactivate it downstream.","summary":"Hedgehog ligands bind Patched (PTCH1), relieving inhibition of Smoothened (SMO), which activates GLI transcription factors. PTCH1 loss or SMO mutation drives basal cell carcinoma (Gorlin syndrome) and the SHH subgroup of medulloblastoma. SMO inhibitors vismodegib and sonidegib are approved for advanced BCC; glasdegib is approved in AML with low-dose cytarabine. Resistance arises via SMO mutations or SUFU/GLI2 alterations downstream; stromal Hedgehog signalling in pancreatic cancer had paradoxical tumour-restraining effects, and SMO inhibitors failed there.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Hedgehog_signaling_pathway","links":[{"label":"Sekulic et al., Vismodegib in advanced basal-cell carcinoma (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1113713"}],"tags":["mechanism"],"related":[],"cancers":["glioblastoma","aml"],"sections":[],"technologies":["kinase-inhibitors","hedgehog-inhibitors"],"targets":["ptch1"],"drugs":[],"companies":[],"institutions":["stanford","dana-farber"],"pathways":["wnt","notch","cancer-stem-cells-plasticity"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Leading programmes: Scott (Stanford) and Oro (Stanford) on Hedgehog in skin; Beachy (Stanford, cyclopamine); Rudin/Pomeroy on SHH medulloblastoma."],"analogy":"A construction crew that is supposed to leave once the building is finished. In these cancers the foreman (SMO) never gets the 'stop' message from the site manager (PTCH1).","nodes":[{"id":"shh","label":"SHH ligand","x":15,"y":30},{"id":"ptch","label":"PTCH1","x":38,"y":30},{"id":"smo","label":"SMO","x":60,"y":30},{"id":"sufu","label":"SUFU","x":60,"y":65},{"id":"gli","label":"GLI1/2","x":82,"y":50},{"id":"out","label":"Proliferation (BCC, SHH-medulloblastoma)","x":82,"y":85}],"edges":[{"from":"shh","to":"ptch","type":"inhibits"},{"from":"ptch","to":"smo","type":"inhibits"},{"from":"smo","to":"gli","type":"activates"},{"from":"sufu","to":"gli","type":"inhibits"},{"from":"gli","to":"out","type":"activates"}],"interventions":["SMO inhibitors vismodegib, sonidegib (advanced BCC), glasdegib (AML)","GLI inhibitors (arsenic trioxide, BET inhibitors) for downstream resistance (investigational)","Surgery and radiation remain first line for most BCC"]},"route":"/pathways/hedgehog/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"atrt","kind":"cancer","name":"Atypical teratoid/rhabdoid tumour (ATRT)","route":"/cancers/atrt/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"locally-advanced-bcc","kind":"cancer","name":"Locally advanced and metastatic basal cell carcinoma","route":"/cancers/locally-advanced-bcc/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"medulloblastoma-shh","kind":"cancer","name":"SHH-activated medulloblastoma","route":"/cancers/medulloblastoma-shh/"}],"technology":[{"id":"hedgehog-inhibitors","kind":"technology","name":"Hedgehog pathway inhibitors","route":"/technologies/hedgehog-inhibitors/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"gli1","kind":"target","name":"GLI1","route":"/targets/gli1/"},{"id":"ptch1","kind":"target","name":"PTCH1 (Patched 1)","route":"/targets/ptch1/"},{"id":"sufu","kind":"target","name":"SUFU","route":"/targets/sufu/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"stanford","kind":"institution","name":"Stanford Health Care / Stanford Cancer Institute","route":"/institutions/stanford/"}],"pathway":[{"id":"basal-cell-carcinoma-signalling","kind":"pathway","name":"Basal cell carcinoma (KEGG map)","route":"/pathways/basal-cell-carcinoma-signalling/"},{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"id":"notch","kind":"pathway","name":"Notch signalling","route":"/pathways/notch/"},{"id":"proteoglycans-in-cancer","kind":"pathway","name":"Proteoglycans in cancer","route":"/pathways/proteoglycans-in-cancer/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"paper":[{"id":"paper-olive-hedgehog-stroma-gemcitabine-delivery-science-2009","kind":"paper","name":"Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer","route":"/key-papers/paper-olive-hedgehog-stroma-gemcitabine-delivery-science-2009/"},{"id":"paper-rhim-stroma-restrains-pancreatic-cancer-cell-2014","kind":"paper","name":"Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma","route":"/key-papers/paper-rhim-stroma-restrains-pancreatic-cancer-cell-2014/"}],"term":[{"id":"cancer-stem-cell-theory","kind":"term","name":"Cancer stem cell theory and phenotypic plasticity","route":"/terms/cancer-stem-cell-theory/"},{"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/"}]}}