One of the emerging themes in cancer biology is the dependence of cancer subtypes on certain signaling pathways for continued tumor growth. For example, mutations that activate the Hh signaling pathway drive growth of a variety of cancers including basal cell carcinoma (BCC), medulloblastoma, pancreatic, prostate, and small cell lung cancer that account for up to 25% of all human cancer deaths. Despite the critical nature of Hh signaling, how Hh mediates tumor proliferation remains poorly understood. Use of Smo antagonists are effective in treating advanced or metastatic BCC, however early tumor resistance in about 20% of patients illustrates the need for additional targets for therapy. I have identified aPKC as a novel Hh target gene and activator of Hh signaling. aPKC forms a positive feedback loop by phosphorylating and activating Gli1, resulting in an increase in DNA binding and transcriptional activity. Smo antagonist-sensitive and resistant BCCs upregulate aPKC activity to drive high levels of Hh signaling for continued growth. Application of topical aPKC inhibitors suppress signaling and growth of murine tumors and Smo-resistant BCC cell lines, implicating aPKC as a new, tumor-selective therapeutic target for the treatment of Hh-dependent cancers. I am currently identifying new aPKC inhibitors, determining how cancer promotes kinase activity, and how substrate phosphorylation drives tumor growth.