Summary The Hedgehog (Hh) signaling pathway governs complex developmental processes, including proliferation and patterning within diverse tissues. These activities rely on a tightly-regulated transduction system that converts graded Hh input signals into specific levels of pathway activity. Uncontrolled activation of Hh signaling drives tumor initiation and maintenance. However, recent entry of pathway-specific inhibitors into the clinic reveals mixed patient responses and thus prompts further exploration of pathway activation and inhibition. In this review, we share emerging insights on regulated and oncogenic Hh signaling, supplemented with updates on the development and use of Hh pathway-targeted therapies.

Aberrant Shh signaling promotes tumor growth in diverse cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy and the mechanisms of resistance remain poorly understood. Using new medulloblastoma models, we identify two distinct paradigms of resistance to Smo inhibition. Sufu mutations lead to maintenance of the Shh pathway in the presence of Smo inhibitors. Alternatively activation of the RAS/MAPK pathway circumvents Shh pathway-dependency, drives tumor growth and enhances metastatic behavior. Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activation emerged from the antecedent BCC tumors. Together these findings reveal a critical role of RAS/MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors.

In glioblastoma, PI3kinase (PI3K) signaling is frequently activated by loss of the tumor suppressor PTEN1. However, it is not known whether inhibiting PI3K represents a selective and effective approach for treatment. Here we interrogate large databases and find that Shh signaling is activated in PTEN-deficient glioblastoma. We demonstrate that Shh and PI3K pathways synergize to promote tumor growth and viability in human PTEN-deficient glioblastomas. A combination of PI3K and Shh signaling inhibitors not only suppresses activation of both pathways, but also abrogates S6kinase signaling. Accordingly, simultaneously targeting both pathways results in mitotic catastrophe and tumor apoptosis, and dramatically reduces growth of PTEN-deficient glioblastomas in vitro and in vivo. The drugs tested here appear safe in humans; therefore this combination may provide new targeted treatment for glioblastoma.