The Hedgehog Pathway in Cancer: From Basal Cell Carcinoma to Resistance

How the Pathway Works

The receptor PTCH1 normally holds the signalling protein SMO inactive at the primary cilium. When a Hedgehog ligand (Sonic, Indian or Desert Hedgehog) binds PTCH1, that inhibition is released, SMO becomes active, and the GLI transcription factors switch from repressor to activator forms.

Active GLI drives target genes including PTCH1 itself and GLI1, creating feedback, plus proliferation genes such as cyclin D and, in some contexts, components that sustain a stem-like state.

Mutations That Lock It On

Loss-of-function mutations in PTCH1 remove the brake on SMO, and activating mutations in SMO make it constitutively active. Either produces ligand-independent pathway activity.

Germline PTCH1 mutations cause Gorlin syndrome (nevoid basal cell carcinoma syndrome), with numerous basal cell carcinomas, jaw cysts and a risk of medulloblastoma.

Where It Matters Clinically

Nearly all basal cell carcinomas have Hedgehog pathway activation, usually through PTCH1 loss. The SHH-subgroup of medulloblastoma is defined by pathway activation, through PTCH1, SMO, SUFU or GLI2 alterations depending on patient age.

Pathway activity is also reported in some pancreatic, lung and other cancers, but often reflects paracrine signalling to the stroma rather than a tumour-cell driver, and inhibitors have not shown benefit there.

SMO Inhibitors and Resistance

Vismodegib and sonidegib bind SMO and are approved for locally advanced or metastatic basal cell carcinoma and, for one agent, adult SHH medulloblastoma. Muscle spasms, hair loss and taste changes are common effects.

Resistance develops through SMO mutations that block drug binding, amplification of GLI2 or downstream components, or activation of the pathway below SMO, for example via SUFU loss, which cannot be overcome by an SMO inhibitor.

Interpretation Notes

A Hedgehog pathway alteration is most actionable when it sits at or above SMO in a basal cell carcinoma or SHH medulloblastoma; downstream lesions such as SUFU loss predict lack of SMO-inhibitor benefit.

Pathway activity signatures in other cancers are research findings, not treatment indications.

Key Takeaways

• ·PTCH1 normally inhibits SMO; a Hedgehog ligand or PTCH1 loss releases SMO to activate GLI.
• ·PTCH1 loss or SMO activation drives basal cell carcinoma and SHH medulloblastoma.
• ·SMO inhibitors (vismodegib, sonidegib) treat advanced basal cell carcinoma.
• ·Resistance via SMO mutation or downstream lesions such as SUFU loss limits these drugs.