Hedgehog signalling
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.
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.
In one picture
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).
Diagram
top- 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
Notes
top- Leading programmes: Scott (Stanford) and Oro (Stanford) on Hedgehog in skin; Beachy (Stanford, cyclopamine); Rudin/Pomeroy on SHH medulloblastoma.