It now appears that constitutive activation of Hedgehog signalling, by inactivating mutations in PTCH1 or activating mutations in the coreceptor SMOH, is required and possibly sufficient for basal cell carcinoma development and also contributes to the formation of a variety of other tumour types, including medulloblastoma and rhabdomyosarcoma.
In mice, an mTORC1 inhibitor suppressed medulloblastoma driven by a mutant SMO that is inherently resistant to existing SMO inhibitors, prolonging the survival of the mice.
The FDA‑approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH‑GLI signaling status.
Hh signaling is upregulated in basal cell carcinoma and medulloblastoma and Hh pathway inhibitors targeting the Smoothened (SMO) protein are in clinical use.