Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors

Abstract

The sonic hedgehog (Shh) signaling pathway is a major regulator of cell differentiation, cell proliferation, and tissue polarity. Aberrant activation of the Shh pathway has been shown in a variety of human cancers, including, basal cell carcinoma, malignant gliomas, medulloblastoma, leukemias, and cancers of the breast, lung, pancreas, and prostate. Tumorigenesis, tumor progression and therapeutic response have all been shown to be impacted by the Shh signaling pathway. Downstream effectors of the Shh pathway include smoothened (SMO) and glioma-associated oncogene homolog (GLI) family of zinc finger transcription factors. Both are regarded as important targets for cancer therapeutics. While most efforts have been devoted towards pharmacologically targeting SMO, developing GLI-targeted approach has its merit because of the fact that GLI proteins can be activated by both Shh ligand-dependent and -independent mechanisms. To date, two SMO inhibitors (LDE225/Sonidegib and GDC-0449/Vismodegib) have received FDA approval for treating basal cell carcinoma while many clinical trials are being conducted to evaluate the efficacy of this exciting class of targeted therapy in a variety of cancers. In this review, we provide an overview of the biology of the Shh pathway and then detail the current landscape of the Shh-SMO-GLI pathway inhibitors including those in preclinical studies and clinical trials.

Keywords: GLI; PTCH; inhibitors; smoothened; sonic hedgehog pathway; tGLI1; targeted therapy.

Figure 1

Inhibition of components of the Shh Pathway in cancer. Inactive signaling (left) occurs in the absence of Shh ligand wherein PTCH1 inhibits SMO resulting in GLI1 sequestration in the cytoplasm by SUFU. In the presence of Shh (right), PTCH1 suppression of SMO is abrogated resulting in the nuclear accumulation of GLI1 and activation of target genes that promote several oncogenic properties to tumor cells. Inhibition of the Shh pathway is primarily directed at inhibition of SMO and GLI1, with many of these compounds in clinical trials for solid cancers. More recently attempts have been made to inhibit the Shh signaling pathway by using the monoclonal antibody 5E1 or the SHHat inhibitor RU-SKI 43 to inhibit SHH directly. SHHat is an O-acyltransferase that catalyzes the palmitoylation of Shh, which is critical to its function.