Targeting oncogenic Hedgehog signaling. (a) In normal cells the Patched homolog, PTCH1, blocks the activation of the Smoothened homolog, SMO. Binding of Hedgehog ligand to PTCH1 removes the repression of SMO, and this drives transcriptional changes via the activity of GLI proteins. (b) In tumors such as basal-cell carcinoma and medulloblastoma, mutations in PTCH1 or SMO lead to constitutive, ligand-independent signaling and an addiction to hedgehog signaling. (c) Blocking the activity of SMO with a small molecule, GDC-0449 can ablate hedgehog signaling and thus inhibit cell growth in addicted tumor cells.
Lord and Ashworth BMC Biology 2010 8:38 doi:10.1186/1741-7007-8-38