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Unraveling the therapeutic potential of the Hedgehog pathway in cancer

Abstract

Major progress has been made in recent years in the development of Hedgehog (Hh) pathway inhibitors for the treatment of patients with cancer. Promising clinical trial results have been obtained in cancers that harbor activating mutations of the Hh pathway, such as basal cell carcinoma and medulloblastoma. However, for many cancers, in which Hh ligand overexpression is thought to drive tumor growth, results have been disappointing. Here we review the preclinical data that continue to shape our understanding of the Hh pathway in tumorigenesis and the emerging clinical experience with smoothened inhibitors.

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Figure 1: The mammalian Hh signaling pathway: key components and signal transduction.
Figure 2: Proposed mechanisms of Hh pathway activation in cancer.
Figure 3: Targeting aberrant Hh pathway activity.
Figure 4: Acquired resistance to SMO inhibitors and approaches to overcome resistance.

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Acknowledgements

We thank S. Buonamici for her contributions to the figure design and J. Brechbiel for medical editorial assistance with this manuscript. Financial support for editorial assistance was provided by Novartis Pharmaceuticals Corporation.

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Correspondence to Marion Dorsch.

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D.A. and Z.J. have declared competing financial interest as employees of Novartis Pharmaceuticals Corporation.

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Amakye, D., Jagani, Z. & Dorsch, M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med 19, 1410–1422 (2013). https://doi.org/10.1038/nm.3389

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