Protein kinase A activation inhibits oncogenic S onic hedgehog signalling and suppresses basal cell carcinoma of the skin

Basal cell carcinoma of the skin ( BCC ) is caused by constitutive activation of the S onic hedgehog ( S hh) pathway, mainly through mutations either in the S hh receptor P atched ( PTCH ) or in its co‐receptor S moothened ( S mo). Inhibitors of this pathway that are currently in clinical trials inhibit S mo. However, mutations in S mo can result in resistance to these inhibitors. To target most BCC s and avoid acquired resistance because of S mo mutations, inhibiting the S hh‐pathway downstream of S mo is critical. Attractive downstream targets would be at the level of G li proteins, the transcriptional activators of this pathway in BCC s. Previously it has been shown that G li1 and G li2, when phosphorylated by protein kinase A ( PKA ), are targeted for proteosomal degradation. Here we show that PKA activation via the c AMP agonist forskolin is sufficient to completely abolish oncogenic S mo activity in vitro . In an inducible BCC mouse model due to a S mo mutation that confers resistance to current S mo inhibitors, topical forskolin treatment significantly reduced G li1 m RNA levels and resulted in strongly suppressed BCC tumor growth. Our data show that forskolin inhibits the growth of even those BCC s that are resistant to S mo inhibitors and provide a proof‐of‐principle framework for the development of topically applied human skin‐permeable novel pharmacologic inhibitors of oncogenic S hh‐signaling through PKA activation.