www.jcb.org/cgi/doi/10.1083/jcb.201207140 JCB 193

One of the emerging themes in cancer biology is the depen-dence of cancer subtypes on certain signaling pathways for con-tinued tumor growth. For example, mutations that activate the Hedgehog (Hh) signaling pathway drive growth of a variety of cancers including basal cell carcinomas (BCCs) and medullo-blastomas, along with pancreatic, prostate, and small cell lung cancer that account for up to 25 % of all human cancer deaths (Epstein, 2008). BCCs are the most prevalent cancer in the world, and nearly half of all US citizens are likely to develop this cancer before retirement (National Cancer Institute, 2010). Twenty years of extensive research identifying Hh pathway components and their functional roles recently culminated in the newly FDA approved Hh pathway antagonist vismodegib (Erivedge; Genentech/Roche) for the treatment of locally advanced or metastatic BCCs. Although vismodegib and other Smo in