Targeting hedgehog signaling in cancer: research and clinical developments

Abstract

Since its first description in Drosophila by Drs Nusslein-Volhard and Wieschaus in 1980, hedgehog (Hh) signaling has been implicated in regulation of cell differentiation, proliferation, tissue polarity, stem cell maintenance, and carcinogenesis. The first link of Hh signaling to cancer was established through studies of Gorlin syndrome in 1996 by two independent teams. Later, it was shown that Hh signaling may be involved in many types of cancer, including skin, leukemia, lung, brain, and gastrointestinal cancers. In early 2012, the US Food and Drug Administration approved the clinical use of Hh inhibitor Erivedge/vismodegib for treatment of locally advanced and metastatic basal cell carcinomas. With further investigation, it is possible to see more clinical applications of Hh signaling inhibitors. In this review, we will summarize major advances in the last 3 years in our understanding of Hh signaling activation in human cancer, and recent developments in preclinical and clinical studies using Hh signaling inhibitors.

Keywords: PTCH1; animal model; cancer; clinical trials; hedgehog; signal transduction; smoothened.

Figure 1

A diagram of hedgehog (Hh) signaling in mammalian cells. Smoothened (SMO) is the key signal transducer of the Hh pathway. In the absence of the Hh ligands, Hh receptor patched (PTC) is thought to be localized in the cilium to inhibit SMO signaling. Coreceptors of Hh include CDO (cell adhesion molecule-related/down regulated by oncogenes), brother of CDO (BOC), Gas1, glypican 3, (GPC3), and GPC5. Wnt inhibitory factor-1 (WIF1) can also regulate Hh signaling through association with CDO, BOC, or GPC5. Gli molecules are processed with the help of suppressor of fused (SuFu)/KIF7, β-TRCP molecules into repressor forms, which turn off the Hh signaling pathway. Other negative regulators of Gli molecules include Rab23, protein kinase A (PKA), SuFu, tumor suppressor sucrose nonfermenting 5 (SNF5), Culin 3 (Cul3), and itchy E3 ubiquitin ligase (Itch) through regulation Gli protein modifications, nuclear–cytoplasm shuttling, as well as transcriptional activities. In the presence of Hh, PTC is thought to be shuttled out of cilium and is unable to inhibit SMO. The ciliary localization of SMO is thought to require β-arrestin 2 (βArr2), and G protein coupled receptor kinase 2 (GRK2). Hh reception promotes SMO conformational changes to form dimers. Gli molecules are now processed to active forms (GliA), which will activate the Hh target genes. This process can be inhibited by KIF7 and SuFu. Protein kinase C isoform ι/λ0 (PKCι/λ) is known to positively regulate Gli transcriptional activity. Positive regulators are in red, negative regulators are in blue, and target genes are in pink. KIF7 can function (in black) as a negative regulator or a positive regulator. The interacting pathways with the Hh pathway are in green. Although the role of cilium for Hh signaling during embryonic development is well established, cancer cells generally lack cilia. It has been demonstrated that lack of cilia prevents development of basal cell carcinomas in mice. It is not clear whether this is true for all other types of Hh signaling-associated cancer. Abbreviations: EGF, epidermal growth factor; EMT, epithelial–mesenchymal transition; IGF, insulin-like growth factor; PDGF, platelet-derived growth factor; TGFβ, transforming growth factor β; VEGF, vascular endothelial growth factor; GDC0449, synthetic small molecules targeting at SMO signaling; BMS833932, synthetic small molecules targeting at SMO signaling; LY2940680 synthetic small molecules targeting at SMO signaling; SAG, smoothened agonist; MDM2, Mouse double minute 2 homolog; PI3K, Phosphatidylinositide 3-kinases; AKT, homolog of viral oncogene v-AKT; MEK, MAPK or ERK kinase; Stat3, signal transducer and activator of transcription 3; Wnt wingless homolog; ABCG2, ATP-binding cassette sub-family G member 2; BCL2, B-cell lymphoma 2; bTRCP, beta-transducin repeat containing protein.