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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.
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).
Published alongside Ozdemir, it explains why the hedgehog inhibitor trials in patients failed and why stromal targets are now chosen for their signalling rather than their bulk.
It launched a decade of attempts to strip the stroma to let drugs in; the clinical trials that followed failed, and later mouse work showed the stroma also restrains the tumour.
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