Basal cell carcinoma (KEGG map)

The KEGG basal cell carcinoma map (hsa05217) shows almost every BCC as a Hedgehog pathway tumour. Normally the ligand Sonic hedgehog (SHH) binds the receptor PTCH1, which relieves PTCH1's inhibition of the seven-pass receptor SMO; SMO then frees the GLI1, GLI2 and GLI3 transcription factors from SUFU and the KIF7 complex, and GLI drives transcription of proliferation and survival genes (cyclin D, MYC, BCL2 and GLI1 itself). In BCC, inactivating mutations of PTCH1 (the gene behind Gorlin syndrome) or activating mutations of SMO, and less often SHH or SUFU changes, give continuous target gene activation without ligand. Ultraviolet exposure is the main environmental cause, and the map also draws TP53, which carries UV-signature mutations in more than half of sporadic BCCs. Epstein, Nat Rev Cancer, 2008 (doi:10.1038/nrc2503) reviews the genetics, the mouse models showing that Hedgehog activation in basal keratinocytes is sufficient to produce BCC, and the rationale for SMO antagonists. KEGG also lists canonical WNT and BMP components as context for basal keratinocyte fate.

What drugs do about it: the SMO antagonists vismodegib and sonidegib are approved for locally advanced or metastatic BCC not suitable for surgery or radiotherapy, and produce responses in most Hedgehog-driven tumours. Resistance usually comes from SMO mutations that block drug binding or from downstream SUFU loss and GLI2 amplification. The PD-1 antibody cemiplimab is approved after Hedgehog inhibitor failure or intolerance.