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Review
. 2019 Feb;42(2):263-279.
doi: 10.1007/s40264-018-0777-5.

Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer

Richard L Carpenter  1   2   3 , Haimanti Ray  4
Affiliations
Review

Safety and Tolerability of Sonic Hedgehog Pathway Inhibitors in Cancer

Richard L Carpenter et al. Drug Saf. 2019 Feb.

Abstract

The hedgehog pathway, for which sonic hedgehog (Shh) is the most prominent ligand, is highly conserved and is tightly associated with embryonic development in a number of species. This pathway is also tightly associated with the development of several types of cancer, including basal cell carcinoma (BCC) and acute promyelocytic leukemia, among many others. Inactivating mutations in Patched-1 (PTCH1), leading to ligand-independent pathway activation, are frequent in several cancer types, but most prominent in BCC. This has led to the development of several compounds targeting this pathway as a cancer therapeutic. These compounds target the inducers of this pathway in Smoothened (SMO) and the GLI transcription factors, although targeting SMO has had the most success. Despite the many attempts at targeting this pathway, only three US FDA-approved drugs for cancers affect the Shh pathway. Two of these compounds, vismodegib and sonidegib, target SMO to suppress signaling from either PTCH1 or SMO mutations that lead to upregulation of the pathway. The other approved compound is arsenic trioxide, which can suppress this pathway at the level of the GLI proteins, although current evidence suggests it also has other targets. This review focuses on the safety and tolerability of these clinically approved drugs targeting the Shh pathway, along with a discussion on other Shh pathway inhibitors being developed.

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Conflict of interest statement

Conflict of Interest: Richard L Carpenter and Haimanti Ray have no conflicts of interests to declare.

Figures

Figure 1.
Figure 1.
The Sonic Hedgehog Pathway. A) In the absence of Shh ligand, PTCH1 suppresses SMO allowing for SUFU suppression of GLI1. B) In the presence of Shh ligand, PTCH1 repression of SMO is removed allowing for SMO to repress SUFU leading to the release and nuclear translocation of GLI1. GLI1, and the other GLI proteins then promote a gene expression program that promotes multiple cancer phenotypes. The inhibitors to this pathway, the FDA-approved inhibitors highlighted in green, primarily have targeted SMO with some attempts to target Shh itself and the GLI proteins, but with little success.
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