The Hedgehog Signaling Pathway in Cancer

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The Hedgehog Signaling Pathway in Cancer Published OnlineFirst June 19, 2012; DOI: 10.1158/1078-0432.CCR-11-2509 Clinical Cancer Molecular Pathways Research Molecular Pathways: The Hedgehog Signaling Pathway in Cancer Ross McMillan and William Matsui Abstract The Hedgehog (Hh) signaling pathway regulates embryonic development and may be aberrantly activated in a wide variety of human cancers. Efforts to target pathogenic Hh signaling have steadily progressed from the laboratory to the clinic, and the recent approval of the Hh pathway inhibitor vismodegib for patients with advanced basal cell carcinoma represents an important milestone. On the other hand, Hh pathway antagonists have failed to show significant clinical activity in other solid tumors. The reasons for these negative results are not precisely understood, but it is possible that the impact of Hh pathway inhibition has not been adequately measured by the clinical endpoints used thus far or that aberrancies in Hh signal transduction limits the activity of currently available pathway antagonists. Further basic and correlative studies to better understand Hh signaling in human tumors and validate putative antitumor mechanisms in the clinical setting may ultimately improve the success of Hh pathway inhibition to other tumor types. Clin Cancer Res; 18(18); 4883–8. Ó2012 AACR. Background and GLI3 represses Hh target genes that include GLI1, PTCH1 Cyclin D1 c-Myc Bcl-2 The Hedgehog (Hh) signaling pathway is highly con- , , , and , whereas GLI2 can act served from flies to humans and is essential for develop- in either a positive or negative manner depending on ment of the normal embryo (1, 2). In mammals, Hh posttranscriptional and posttranslational processing events signaling regulates both patterning and polarity events (4). Vertebrate Hh signaling is further regulated by the during early embryogenesis and the morphogenesis of translocation of signaling components among the cyto- specific organs and tissues. The pathway is subsequently plasm, plasma membrane, nucleus, and primary cilium silenced in most adult tissues but can be reactivated fol- that acts as a sensor to monitor the extracellular environ- lowing injury to promote repair and regeneration. Further- ment (5). PTCH1 is initially located in the primary cilium more, aberrant Hh signaling has been detected in many and SMO within cytoplasmic vesicles. Following ligand human cancers, suggesting a broad role in carcinogenesis. binding to PTCH1, SMO moves to the primary cilium, where it interacts with the GLI processing complex that Hh signal transduction eventually results in the nuclear translocation of the GLI Hh signaling is initiated by binding of one of the 3 soluble transcriptional regulators (6). and lipid modified HH ligands (Sonic, Indian, or Desert HH) found in vertebrates to the 12-pass transmembrane The Hh pathway and cancer receptor Patched (PTCH1, Fig. 1). In the absence of ligand, A role for Hh signaling in cancer was initially provided by PTCH1 represses the 7-pass transmembrane G-protein– studies in Gorlin syndrome, an autosomal dominant dis- coupled receptor (GPCR)-like protein Smoothened (SMO). order characterized by craniofacial and skeletal abnormal- Ligand binding relieves this inhibition and allows SMO to ities and a markedly increased risk of advanced basal cell modulate a cytoplasmic complex containing Suppressor of carcinoma (BCC) and medulloblastoma (7, 8). The discov- Fused (SUFU) that modifies the 3 glioma-associated (GLI) ery of PTCH1 mutations as the cause of Gorlin syndrome transcriptional regulators through phosphorylation, suggested that dysregulated Hh pathway activity was sumoylation, and selective proteolysis (3). GLI1 induces responsible for the development of these cancers (9, 10), and these findings were substantiated by the identification of PTCH1, SMO, and to a lesser extent, SUFU mutations in Authors' Affiliation: The Sidney Kimmel Comprehensive Cancer Center approximately 90% and 15% to 30% of spontaneously and Department of Oncology, Johns Hopkins University School of Med- icine, Baltimore, Maryland arising BCCs and medulloblastomas, respectively (11, 12). Furthermore, the recapitulation of BCC and medullo- Corresponding Author: William Matsui, The Sidney Kimmel Comprehen- sive Cancer Center, Department of Oncology, Johns Hopkins University blastoma in transgenic mouse models has provided defin- School of Medicine, CRB245, 1650 Orleans Street, Baltimore, MD 21287. itive proof that PTCH1 and SMO mutations are a causal Phone: 410-955-2808; Fax: 410-614-7279; E-mail: [email protected] factor in these tumor types. doi: 10.1158/1078-0432.CCR-11-2509 Aberrant Hh pathway activity is also a feature of many Ó2012 American Association for Cancer Research. other human cancers. However, activating mutations in www.aacrjournals.org 4883 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst June 19, 2012; DOI: 10.1158/1078-0432.CCR-11-2509 McMillan and Matsui Cyclopamine Robotnikinin GDC-0449 5Eh1 Ab LDE225 PF04449913 ABTAK-441 IPI-926 HH PTCH1 SMO PTCH1 SMO HPI Arsenic Itraconazole SUFU SUFU SUFU GLIr GLIa GLIa Nucleus Nucleus GANT-61 GLIr GLIa Hh target genes off Hh target genes on © 2012 American Association for Cancer Research Figure 1. The Hh signaling pathway. Positive and negative regulatory components are depicted in green and red, respectively. A, in the absence of HH ligand, PTCH1 inhibits SMO allowing the GLI processing complex containing SUFU to generate transcriptional repressors (GLIr). B, HH ligand binding to PTCH depresses SMO and generates activated GLI factors (GLIa) that induce the expression of Hh target genes. Clinical and preclinical inhibitors of pathway signaling are listed at their sites of pathway activity. HPI, hedgehog pathway inhibitor. pathway components are uncommon, and overexpression cells secreting HH ligands that activate signaling within of HH ligands is thought to drive increased pathway activity. stromal cells to produce secondary factors supporting In these "ligand-dependent" tumors, several types of Hh angiogenesis and tumor cell proliferation and survival signaling have been described. Autocrine and juxtacrine (20, 21). signaling in which tumor cells both secrete and respond The Hh pathway can also regulate cancer stem cells (CSC) to HH ligands has been reported in many cancers, including with enhanced tumor initiating and self-renewal potential. small cell lung, pancreas, colorectal, and metastatic prostate In multiple myeloma, Hh pathway activation induces the carcinomas as well as melanoma and glioblastoma (13– expansion of CSCs, whereas pathway inhibition results in 18). Paracrine signaling in which the cells secreting ligands terminal differentiation, loss of self-renewal, and exhaus- are distinct from those responding with pathway activation tion of the malignant clone (22). Studies in chronic myeloid has also been described in lymphoma and multiple mye- leukemia (CML) and breast cancer have similarly found that loma, in which HH ligands produced by stromal cells in the Hh pathway inhibition limits tumorigenic potential and local microenvironment induce pathway activity in tumor self-renewal (23–25). Emerging data suggest that CSCs in cells (19). Alternatively, studies in epithelial cancers have solid tumors are involved in metastatic disease progression found that paracrine Hh signaling is reversed with tumor (26), and the Hh pathway has been found to regulate the 4884 Clin Cancer Res; 18(18) September 15, 2012 Clinical Cancer Research Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst June 19, 2012; DOI: 10.1158/1078-0432.CCR-11-2509 Hedgehog Signaling and Cancer epithelial–mesenchymal transition and dissemination of The SMO antagonist PF-04449913 (Pfizer) has also pro- CSCs in pancreatic and colorectal carcinoma (15, 27). vided encouraging early results in patients with hemato- Therefore, the Hh signaling pathway may specify CSC fate logic malignancies (42). In this dose–escalation phase I decisions similar to its role in development. trial, 32 patients representing a variety of diseases, including Most studies have focused on canonical Hh signaling acute myeloid leukemia, myelodysplastic syndrome, mye- events, but GLI-independent effects have been identified in lofibrosis, CML, and chronic myelomonocytic leukemia normal cells that may contribute to its pathogenic role in (CMMoL), received PF-04449913 as a single agent. cancer. For example, SMO has been found to activate the Responses were observed across all diseases as evidenced RhoA and Rac1 GTPases to induce cytoskeletal remodeling, by decreased leukemic blast counts and/or improvements fibroblast migration, and endothelial tubulogenesis (28, in normal hematopoiesis, and a patient with transformed 29). In addition, PTCH1 has been found to act as a depen- CMMoL achieved a complete response. dence receptor that directly triggers apoptosis in the absence Mechanisms of clinical resistance have also been reported of ligand, whereas ligand binding induces canonical target in a patient with metastatic medulloblastoma who became gene expression (30). Therefore, noncanonical effects unresponsive to vismodegib after 3 months of therapy (43). should be further studied in human cancers and, along Serial tumor biopsies identified a novel SMO mutation at with variations in the mode of canonical pathway activa- relapse that interferes with vismodegib binding, and sub- tion,
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