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

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. attempts at targeting this pathway, there are only three FDA-approved drugs for cancers that 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 (ATO), 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 efficacy and safety of these clinically-approved drugs targeting the Shh pathway along with a discussion on other Shh pathway inhibitors being developed. 1.?Introduction The hedgehog pathway is a highly conserved signaling pathway that is linked to many biological processes. This signaling pathway has been linked to development in many species, including humans (1). It has been linked to growth and patterning in many of these multicellular species including the development of the neural system and bone development (2, 3). The hedgehog pathway and its components have also been linked to several diseases, prominently including human cancer (4). Because of the importance of this pathway to human cancer, there have been several attempts to target this pathway for cancer therapies with few successes and many failures. In this review, we aim to provide an update on the successful agents targeting the hedgehog pathway that have been FDA approved for treatment in human cancers. We will also briefly discuss agents that are currently being developed to target this pathway for the treatment of cancer. 2.?The Hedgehog Pathway in Cancer Mammalian hedgehog signaling can be initiated by three unique ligands in Sonic Hedgehog (Shh), Indian hedgehog, and Desert hedgehog. However, Shh is the most widely expressed and also the most potent of these ligands (1, 5). The ligand Shh is expressed as an inactive full-length protein that is proteolytically cleaved to two proteins and the N-terminal 19 kDa fragment is the active Shh ligand (6). The receptor for this active Shh ligand is Patched1 (PTCH1), a 12-transmembrane protein that binds Shh ligand. Binding of Shh to PTCH1 relieves repression of Smoothed (SMO) by PTCH1 thereby activating SMO signaling activity (Figure 1). The activation of SMO ultimately decreases the interaction between suppressor of fused homolog (SUFU) and GLI proteins that allows GLI proteins to enter the nucleus and bind transcriptional targets to regulate cellular gene expression. There are three GLI isoforms in mammals in GLI1-3 wherein gene expression can be induced by GLI1 and repressed by GLI3 whereas GLI2 can regulate expression in either direction. The GLI proteins are the terminal effectors of the Shh signaling pathway and regulate genes that control organismal patterning and development. Many of the genes regulated by GLI proteins are co-opted by cancer cells as they regulate several cancer-related processes including proliferation, migration and invasion, as well as neovascularization (4). Open in a separate window 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 KN-93 green, primarily have targeted SMO with some KN-93 KN-93 attempts to target Shh itself and the GLI proteins, but with little success. There have been numerous reports of genetic alterations in key components of the Shh pathway in different tumor types NOX1 that leads to constitutive signaling of this pathway and that paracrine signaling of Shh may be an important factor in multiple tumor types (7, 8). While there are reports of the Shh pathway being modified in several tumor types such as breast, pancreatic, colorectal, and rhabdomyosarcoma among several, genetic alterations in this pathway are most consistently seen in basal cell carcinomas (BCCs).