Targeting the Hedgehog Pathway in Cancer: Current Evidence and Future Perspectives

Abstract

The Hedgehog pathway (HhP) plays an important role in normal embryonic development and its abnormal function has been linked to a variety of neoplasms. Recently, the complex mechanisms involved in this pathway have been deciphered and the cross talks with other important pathways involved in carcinogenesis have been characterized. This knowledge has led to the development of targeted therapies against key components of HhP, which culminated in the approval of vismodegib for the treatment of advanced basal cell carcinoma in 2012. Since then, other compounds have been developed and evaluated in preclinical and clinical studies with interesting results. Today, several medications against components of the HhP have demonstrated clinical activity as monotherapies and in combination with cytotoxic treatment or other targeted therapies against mitogenic pathways that are linked to the HhP. This review aims to clarify the mechanism of the HhP and the complex crosstalk with others pathways involved in carcinogenesis and to discuss both the evidence associated with the growing number of medications and combined therapies addressing this pathway and future perspectives.

Keywords: GLI; Hedgehog; SMO inhibitor; targeted therapy.

Figure 1

A simplified model for canonical HhP. (A) The Hedgehog receptor PTCH1 inhibits SMO signaling in the absence of the Hedgehog ligand, which turns off the Hedgehog signaling pathway. (B) In the presence of Hedgehog ligand, PTCH1 stops inhibiting SMO, resulting in the translocation of SMO to the primary cilium. Once activated in the primary cilium, SMO promotes the release of GLI from the SUFU, which allows GLI to enter the nucleus to initiate the transcription program related to HhP. Dysregulation of the HhP has been associated with carcinogenesis.