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The switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.
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.
In plain words · The switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.
The switch in the hedgehog developmental pathway that is stuck on in basal cell carcinoma and some medulloblastomas; three approved pills block it.
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.
4 products aim at Smoothened (hedgehog pathway): small molecules. Drugs bind the molecule precisely: to switch it off, flag the cell for the immune system, or deliver a payload.
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.)
Sources: Human Protein Atlas SMO tissue; Open Targets ENSG00000128602 associations
First described 1996. 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". Source.
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.
RNA: low tissue specificity, detected in many normal tissues.
No normal tissue stained high; medium in Adipose tissue, Adrenal gland, Breast, Caudate, Cerebral cortex, Colon and more.
Medium only: breast cancer, carcinoid, cervical cancer, endometrial cancer.
HPA SMO tissue · HPA SMO pathology · HPA protein class: FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Basal cell carcinoma | 85% | hedgehog pathway activation (PTCH1 or SMO) | doi.org | |
| Medulloblastoma | 30% | SHH subgroup |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Glasdegib is a hedgehog-pathway pill that, with low-dose chemotherapy, extends survival in older AML patients who cannot have intensive treatment; it has largely been displaced by venetoclax combinations.
Patidegib is a hedgehog-pathway blocker made into a skin gel. It is being tested in people with Gorlin syndrome, who grow dozens of basal cell carcinomas, to prevent new tumours without the hair loss, muscle cramps and taste loss that the oral drugs cause.
Sonidegib (Odomzo) is the second hedgehog inhibitor for locally advanced basal cell carcinoma, similar in effect and side effects to vismodegib.
Vismodegib was the first hedgehog-pathway drug, for basal cell carcinomas too advanced for surgery; it shrinks most tumours but muscle cramps, taste loss and hair loss make long-term use hard.
Query for this target: (TITLE:"Smoothened" OR ABSTRACT:"Smoothened" OR TITLE:"hedgehog pathway" OR ABSTRACT:"hedgehog pathway" OR TITLE:"SMO" OR ABSTRACT:"SMO") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Smoothened (hedgehog pathway), not a curated reading list.
Shares Glasdegib, PTCH1 (Patched 1), Patidegib gel in Gorlin syndrome (phase 2A), VISMONEO (vismodegib before surgery for locally advanced basal cell carcinoma).
Shares PTCH1 (Patched 1), Patidegib gel in Gorlin syndrome (phase 2A), VISMONEO (vismodegib before surgery for locally advanced basal cell carcinoma), STEVIE (vismodegib in ordinary practice).
Shares Patidegib, Patidegib gel in Gorlin syndrome (phase 2A), STEVIE (vismodegib in ordinary practice), Why people stop taking hedgehog inhibitors.
Shares VISMONEO (vismodegib before surgery for locally advanced basal cell carcinoma), STEVIE (vismodegib in ordinary practice), BOLT, ERIVANCE BCC.
Shares Patidegib, Patidegib gel in Gorlin syndrome (phase 2A), Locally advanced and metastatic basal cell carcinoma, Basal cell carcinoma.
Shares Vismodegib, Locally advanced and metastatic basal cell carcinoma, Basal cell carcinoma, Small-molecule kinase inhibitors.
Shares Sonidegib, BOLT, Locally advanced and metastatic basal cell carcinoma.
Shares Sonidegib, Vismodegib, SHH-activated medulloblastoma, Medulloblastoma.