• 2D-to-3D Widely-targeted virtual screening
• ADMET
• Cancer
• Combinatorial effect, cyclopamine analogs
• Drug resistance
• FAK inhibitor(s)
• Focal adhesive kinase
• In vitro cell-based assay, MMPBSA method
• Molecular docking
• Molecular dynamics simulation
• SMO inhibitor(s), pharmacological inhibition of FAK and Hh/SMO pathways, Veratrum plant species

• Humans
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Protein Kinase Inhibitors/chemistry
• Protein Kinase Inhibitors/pharmacology
• Cell Line, Tumor
• Alkaloids/chemistry
• Alkaloids/pharmacology
• Signal Transduction/drug effects
• Focal Adhesion Kinase 1/antagonists & inhibitors
• Focal Adhesion Kinase 1/metabolism
• Computer Simulation
• Cell Proliferation/drug effects
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Neoplasms/drug therapy
• Neoplasms/pathology
• Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors
• Focal Adhesion Protein-Tyrosine Kinases/metabolism
• Focal Adhesion Protein-Tyrosine Kinases/chemistry
• Quantitative Structure-Activity Relationship

• Humans
• Carcinoma, Basal Cell/drug therapy
• Carcinoma, Basal Cell/pathology
• Retrospective Studies
• Male
• Female
• Middle Aged
• Aged
• Pyridines/therapeutic use
• Pyridines/administration & dosage
• Anilides/therapeutic use
• Anilides/administration & dosage
• Hedgehog Proteins/antagonists & inhibitors
• Hedgehog Proteins/metabolism
• Skin Neoplasms/drug therapy
• Skin Neoplasms/pathology
• Biphenyl Compounds/therapeutic use
• Adult
• Ubiquinone/analogs & derivatives
• Ubiquinone/therapeutic use
• Ubiquinone/administration & dosage
• Aged, 80 and over
• Neoplasm Metastasis

• National Cancer Institute

• Sjögren’s disease
• TGF-β
• adaptive immunity
• autoimmune disease
• chronic inflammation
• epithelial to mesenchymal transition
• fibrosis
• innate immunity
• myofibroblast
• rheumatic diseases
• rheumatoid arthritis
• systemic lupus erythematosus
• systemic sclerosis

• Humans
• Epithelial-Mesenchymal Transition/physiology
• Autoimmune Diseases
• Sjogren's Syndrome
• Arthritis, Rheumatoid
• Fibrosis
• Extracellular Matrix Proteins

• Cancer pain
• Chronic post-thoracotomy pain
• Neuropathic pain
• Pain processing
• Sonic hedgehog signaling pathway

• chronic obstructive pulmonary disease
• habenula
• hedgehog signaling
• nicotine
• single-cell RNA sequencing

• Mice
• Animals
• Nicotine/pharmacology
• Nicotine/metabolism
• Habenula/metabolism
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Receptors, Nicotinic/metabolism
• Cholinergic Neurons/metabolism
• Lung Diseases/metabolism

• P01 DA047233 NIDA NIH HHS
• R37 DA020686 NIDA NIH HHS
• T32 DA053558 NIDA NIH HHS
• R01 DA045649 NIDA NIH HHS
• R01 DA020686 NIDA NIH HHS
• U01 DA053629 NIDA NIH HHS

• Cholesterol
• Cytoneme
• Hedgehog
• Morphogen
• Patched
• Primary cilia
• Protein kinase A
• Shh
• Smoothened

• Drosophila wing
• hedgehog signaling
• in vivo miRNA sensor toolbox
• miR-10
• miR-958

• Canonical signaling
• Cholesterol
• Hedgehog
• Non-canonical signaling
• Plasma membrane
• Ptch1
• Smo

• Animals
• Cholesterol/metabolism
• Cilia/metabolism
• Embryonic Development
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Signal Transduction/physiology

• PC200160 DOD Prostate Cancer Research Program
• P01 CA217798 NIH HHS
• R21 CA238953 NIH HHS
• RO1 CA247763 NIH HHS
• R01 CA247763 NCI NIH HHS
• R21 CA238953 NCI NIH HHS
• P01 CA217798 NCI NIH HHS
• National Institutes of Health

• bone
• cholesterol
• endochondral ossification
• hedgehog signalling
• osteoarthritis
• smoothened

• Hedgehog
• cholesterol
• coreceptor
• handoff
• lipids
• morphogen
• receptor
• signaling

Hedgehog (Hh) signaling is a highly conserved pathway that plays a vital role during embryonic development. Recently, uncontrolled activation of this pathway has been demonstrated in various types of cancer. Therefore, Hh pathway inhibitors have emerged as an important class of anti-cancer agents. Unfortunately, however, their reputation has been tarnished by the emergence of resistance during therapy, necessitating clarification of mechanisms underlying the drug resistance. In this review, we briefly overview canonical and non-canonical Hh pathways and their inhibitors as targeted cancer therapy. In addition, we summarize the mechanisms of resistance to Smoothened (SMO) inhibitors, including point mutations of the drug binding pocket or downstream molecules of SMO, and non-canonical mechanisms to reinforce Hh pathway output. A distinct mechanism involving loss of primary cilia is also described to maintain GLI activity in resistant tumors. Finally, we address the main strategies to circumvent the drug resistance. These strategies include the development of novel and potent inhibitors targeting different components of the canonical Hh pathway or signaling molecules of the non-canonical pathway. Further studies are necessary to avoid emerging resistance to Hh inhibitors and establish an optimal customized regimen with improved therapeutic efficacy to treat various types of cancer, including basal cell carcinoma.

• basal cell carcinoma
• drug resistance
• hedgehog inhibitor
• hedgehog signaling
• smoothened inhibitor
• targeted cancer therapy

• Animals
• Clinical Trials as Topic
• Drug Resistance, Neoplasm
• Hedgehog Proteins/metabolism
• Humans
• Models, Biological
• Molecular Targeted Therapy
• Signal Transduction

• Activation
• Gi protein
• Smoothened (SMO)
• [35S]-GTPγS binding assay

• Hedgehog Proteins
• Oncogene Proteins/metabolism
• Receptors, G-Protein-Coupled/genetics
• Signal Transduction
• Smoothened Receptor/genetics
• Transcription Factors
• Zinc Finger Protein GLI1

• R35 GM128641 NIGMS NIH HHS

The Hedgehog (Hh) signalling pathway plays a critical role in the growth and patterning during embryonic development and maintenance of adult tissue homeostasis. Emerging data indicate that Hh signalling is implicated in the pathogenesis of inflammatory bowel disease (IBD). Current therapeutic treatments for IBD require optimisation, and novel effective drugs are warranted. Targeting the Hh signalling pathway may pave the way for successful IBD treatment. In this review, we introduce the molecular mechanisms underlying the Hh signalling pathway and its role in maintaining intestinal homeostasis. Then, we present interactions between the Hh signalling and other pathways involved in IBD and colitis-associated colorectal cancer (CAC), such as the Wnt and nuclear factor-kappa B (NF-κB) pathways. Furthermore, we summarise the latest research on Hh signalling associated with the occurrence and progression of IBD and CAC. Finally, we discuss the future directions for research on the role of Hh signalling in IBD pathogenesis and provide viewpoints on novel treatment options for IBD by targeting Hh signalling. An in-depth understanding of the complex role of Hh signalling in IBD pathogenesis will contribute to the development of new effective therapies for IBD patients.

• cilia kinase
• ciliopathy
• endochondral bone formation
• primary cilia
• skeletal ciliopathy
• skeletal dysplasia
• skeletogenesis

To ensure the formation of a properly patterned embryo, multiple processes must operate harmoniously at sequential phases of development. This is implemented by mutual interactions between cells and tissues that together regulate the segregation and specification of cells, their growth and morphogenesis. The formation of the spinal cord and paraxial mesoderm derivatives exquisitely illustrate these processes. Following early gastrulation, while the vertebrate body elongates, a population of bipotent neuromesodermal progenitors resident in the posterior region of the embryo generate both neural and mesodermal lineages. At later stages, the somitic mesoderm regulates aspects of neural patterning and differentiation of both central and peripheral neural progenitors. Reciprocally, neural precursors influence the paraxial mesoderm to regulate somite-derived myogenesis and additional processes by distinct mechanisms. Central to this crosstalk is the activity of the axial notochord, which, via sonic hedgehog signaling, plays pivotal roles in neural, skeletal muscle and cartilage ontogeny. Here, we discuss the cellular and molecular basis underlying this complex developmental plan, with a focus on the logic of sonic hedgehog activities in the coordination of the neural-mesodermal axis.

• cell differentiation
• dermomyotome
• floor plate
• lateral plate mesoderm
• motoneurons
• muscle
• neural tube
• notochord
• sclerotome
• somite

• Hedgehog signaling
• holoprosencephaly
• mathematical modeling
• ultrasensitivity

• G-protein coupled receptor regulation pathway
• GPCR physiological functions
• genome sequences analysis
• insect physiology
• insecticide resistance
• phylogenic tree
• tissue specific expression

• Animals
• Gene Expression Regulation/drug effects
• Insecta/drug effects
• Insecta/genetics
• Insecta/metabolism
• Insecticide Resistance/genetics
• Insecticides/toxicity
• Organ Specificity/drug effects
• Organ Specificity/genetics
• Receptors, G-Protein-Coupled/metabolism

• ALA08-045 and ALA015-1-10026, and ALA015-1-16009 to N.L AAES Hatch/Multistate Grants

ARHGAP36 is an atypical Rho GTPase-activating protein (GAP) family member that drives both spinal cord development and tumorigenesis, acting in part through an N-terminal motif that suppresses protein kinase A and activates Gli transcription factors. ARHGAP36 also contains isoform-specific N-terminal sequences, a central GAP-like module, and a unique C-terminal domain, and the functions of these regions remain unknown. Here we have mapped the ARHGAP36 structure-activity landscape using a deep sequencing-based mutagenesis screen and truncation mutant analyses. Using this approach, we have discovered several residues in the GAP homology domain that are essential for Gli activation and a role for the C-terminal domain in counteracting an N-terminal autoinhibitory motif that is present in certain ARHGAP36 isoforms. In addition, each of these sites modulates ARHGAP36 recruitment to the plasma membrane or primary cilium. Through comparative proteomics, we also have identified proteins that preferentially interact with active ARHGAP36, and we demonstrate that one binding partner, prolyl oligopeptidase-like protein, is a novel ARHGAP36 antagonist. Our work reveals multiple modes of ARHGAP36 regulation and establishes an experimental framework that can be applied towards other signaling proteins.

• Animals
• Cilia/chemistry
• Cilia/genetics
• Cilia/metabolism
• GTPase-Activating Proteins/biosynthesis
• GTPase-Activating Proteins/chemistry
• GTPase-Activating Proteins/genetics
• HEK293 Cells
• Humans
• Mice
• NIH 3T3 Cells
• Protein Domains
• Protein Isoforms
• Signal Transduction
• Structure-Activity Relationship

• T32 CA009302 NCI NIH HHS
• S10 RR027431 NCRR NIH HHS
• P30 CA124435 NCI NIH HHS
• S10 RR025518 NCRR NIH HHS
• R35 GM127030 NIGMS NIH HHS
• T32 GM120007 NIGMS NIH HHS
• National Institute of General Medical Sciences
• National Institutes of Health
• Rachel Molly Markoff Foundation
• Stanford Maternal and Child Health Research Institute
• Alex’s Lemonade Stand Foundation for Childhood Cancer
• Stanford University Robert and Ruth Halperin Graduate Fellowship
• Stanford ChEM‐H Chemistry/Biology Interface Predoctoral Training Program and National Institute of General Medical Sciences
• Stanford Center for Molecular Analysis and Design Fellowship
• Stanford Cancer Biology Training Grant awarded by the National Cancer Institute

Mammalian follicles are composed of oocytes, granulosa cells, and theca cells. Theca cells form in the secondary follicles, maintaining follicular structural integrity and secreting steroid hormones. Two main sources of theca cells exist: Wilms tumor 1 positive (Wt1⁺) cells native to the ovary and Gli1⁺ mesenchymal cells migrated from the mesonephros. Normal folliculogenesis is a process where oocytes, granulosa cells, and theca cells constantly interact with and support each other through autocrine and paracrine mechanisms. The proliferation and differentiation of theca cells are regulated by oocyte-derived factors, including growth development factor 9 and bone morphogenetic protein 15, and granulosa cell-derived factors, including desert hedgehog, Indian hedgehog, kit ligand, insulin-like growth factor 1, as well as hormones such as insulin and growth hormones. Current research on the origin of theca cells is limited. Identifying the origin of theca cells will help us to systematically elaborate the mechanisms of follicular formation and development.

• Animals
• Animals, Genetically Modified
• Catalytic Domain/genetics
• Cells, Cultured
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/antagonists & inhibitors
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/chemistry
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/metabolism
• Embryo, Nonmammalian
• HEK293 Cells
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Humans
• Mice
• Protein Interaction Domains and Motifs/genetics
• Signal Transduction/genetics
• Smoothened Receptor/metabolism
• Smoothened Receptor/physiology
• Zebrafish

• P30 CA042014 NCI NIH HHS
• R35 GM133672 NIGMS NIH HHS
• T32 HD007491 NICHD NIH HHS
• National Institutes of Health
• Defense Sciences Office, DARPA (US)
• National Institute of General Medical Sciences

• GRK2
• Wnt
• asphyxiating thoracic dystrophy
• hedgehog
• smoothened

• Ellis-Van Creveld Syndrome
• G-Protein-Coupled Receptor Kinase 2/genetics
• Hedgehog Proteins/genetics
• Humans
• Mutation
• Wnt Signaling Pathway

• R01 DE019567 NIDCR NIH HHS
• R35 GM118082 NIGMS NIH HHS
• T32 HG002536 NHGRI NIH HHS
• UM1 HG006493 NHGRI NIH HHS
• R01 AR066124 NIAMS NIH HHS
• R01 AR062651 NIAMS NIH HHS
• U24 HG008956 NHGRI NIH HHS

• Hedgehog
• chaperone
• coreceptor
• lipids
• morphogen
• receptor
• signaling

• Nematostella vectensis
• developmental biology
• endomesodermal patterning
• evolutionary biology
• germ cell development
• zygotic hedgehog signaling

• Animals
• Body Patterning/genetics
• Female
• Gene Knockdown Techniques
• Germ Cells/cytology
• Germ Cells/metabolism
• Germ Layers/cytology
• Germ Layers/growth & development
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Life Cycle Stages/genetics
• Male
• Sea Anemones/cytology
• Sea Anemones/genetics
• Sea Anemones/growth & development
• Signal Transduction/genetics

• Stowers Institute for Medical Research

• Baohuoside-I
• Hedgehog
• Smoothened
• epithelial-mesenchymal transition
• nasopharyngeal carcinoma

• Hedgehog
• RND transporter
• cation gradient
• cell signaling
• cholesterol transport

• Compartment boundary
• Drosophila
• Mechanical tension
• Selector genes
• Signaling pathways
• Wing imaginal disc

• Animals
• Biomechanical Phenomena
• Drosophila melanogaster/anatomy & histology
• Drosophila melanogaster/genetics
• Genes, Insect
• Imaginal Discs/metabolism
• Signal Transduction/genetics
• Wings, Animal/metabolism

The Hedgehog (HH) pathway governs cell proliferation and patterning during embryonic development and is involved in regeneration, homeostasis and stem cell maintenance in adult tissues. The activity of this signaling is finely modulated at multiple levels and its dysregulation contributes to the onset of several human cancers. Ubiquitylation is a coordinated post-translational modification that controls a wide range of cellular functions and signaling transduction pathways. It is mediated by a sequential enzymatic network, in which ubiquitin ligases (E3) and deubiquitylase (DUBs) proteins are the main actors. The dynamic balance of the activity of these enzymes dictates the abundance and the fate of cellular proteins, thus affecting both physiological and pathological processes. Several E3 ligases regulating the stability and activity of the key components of the HH pathway have been identified. Further, DUBs have emerged as novel players in HH signaling transduction, resulting as attractive and promising drug targets. Here, we review the HH-associated DUBs, discussing the consequences of deubiquitylation on the maintenance of the HH pathway activity and its implication in tumorigenesis. We also report the recent progress in the development of selective inhibitors for the DUBs here reviewed, with potential applications for the treatment of HH-related tumors.

• DUBs
• Hedgehog pathway
• cancer
• targeted therapy
• ubiquitylation

• Hedgehog reception
• Patched
• cytonemes
• morphogenetic synapsis
• vesicle trafficking

• Animals
• Drosophila Proteins/genetics
• Drosophila Proteins/metabolism
• Drosophila melanogaster
• Endosomal Sorting Complexes Required for Transport/genetics
• Endosomal Sorting Complexes Required for Transport/metabolism
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Imaginal Discs/metabolism
• Protein Transport
• Receptors, Cell Surface/genetics
• Receptors, Cell Surface/metabolism
• SNARE Proteins/genetics
• SNARE Proteins/metabolism
• Wings, Animal

• BFU2015-72831-EXP Spanish Ministry of Economy and Competitiveness (MINECO)
• BFU2017-83789-P Spanish Ministry of Economy and Competitiveness (MINECO)
• BFU2015-73609-JIN Spanish Ministry of Economy and Competitiveness (MINECO)
• RED2018-102411-T Spanish Ministry of Economy and Competitiveness (MINECO)
• SAF2015-71231-REDT Spanish Ministry of Economy and Competitiveness (MINECO)
• Banco de Santander
• CBMSO
• Fundación Areces
• Comunidad de Madrid (Madrid Autonomous Community)
• Amarouto Program
• Spanish Ministry of Economy and Competitiveness (MINECO)
• Comunidad de Madrid (Madrid Autonomous Community)

• BMP
• Dermomyotome
• Dorso-ventral patterning
• Hb9
• Motoneurons
• Myotome
• Neural tube
• Nkx
• Olig2
• Paraxial mesoderm
• Pax7
• Retinoic acid
• Somite

• Animals
• Body Patterning/genetics
• Cell Differentiation/genetics
• Chick Embryo
• Gene Expression Regulation, Developmental
• Hedgehog Proteins/genetics
• Hedgehog Proteins/metabolism
• Mesoderm/metabolism
• Motor Neurons/metabolism
• Neural Plate/metabolism
• Neural Tube/embryology
• Neural Tube/metabolism
• Neurogenesis/genetics
• Neurulation/genetics
• Notochord/metabolism
• Patched-1 Receptor/metabolism
• Quail/embryology
• Signal Transduction/genetics
• Transfection

• Israel Science Foundation

Developmental genes can be coopted to generate evolutionary novelties by changing their spatial regulation. However, developmental genes seldom act independently, but rather work in a gene regulatory network (GRN). How is it possible to recruit a single gene from a whole GRN? What are the properties that allow parallel cooptions of the same genes during evolution? Here, we show that a novel engrailed gene expression underlies a novel wing color pattern in flies. We show that cooption is facilitated 1) because of GRN flexibility over development and 2) because every single gene of the GRN has its own functional time window. We suggest these two temporal properties could explain why the same gene can be independently recruited several times during evolution.

Organisms have evolved endless morphological, physiological, and behavioral novel traits during the course of evolution. Novel traits were proposed to evolve mainly by orchestration of preexisting genes. Over the past two decades, biologists have shown that cooption of gene regulatory networks (GRNs) indeed underlies numerous evolutionary novelties. However, very little is known about the actual GRN properties that allow such redeployment. Here we have investigated the generation and evolution of the complex wing pattern of the fly Samoaia leonensis. We show that the transcription factor Engrailed is recruited independently from the other players of the anterior–posterior specification network to generate a new wing pattern. We argue that partial cooption is made possible because 1) the anterior–posterior specification GRN is flexible over time in the developing wing and 2) this flexibility results from the fact that every single gene of the GRN possesses its own functional time window. We propose that the temporal flexibility of a GRN is a general prerequisite for its possible cooption during the course of evolution.

• cooption
• drosophilids
• gene network
• novelty
• pigmentation

Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

• cellular adaptation
• combination therapy
• resistant mutation
• small molecule inhibitor
• targeted therapy

• R03 CA223545 NCI NIH HHS

• JUN
• bone precursor expansion
• bone precursors
• fractures
• osteoporosis
• osteoprogenitors
• skeletal stem cells
• stem cell therapy

• Gorlin syndrome
• basal cell carcinoma
• hedgehog pathway
• nevoid basal cell carcinoma syndrome
• skin

• Animals
• Basal Cell Nevus Syndrome/metabolism
• Basal Cell Nevus Syndrome/pathology
• Carcinoma, Basal Cell/metabolism
• Carcinoma, Basal Cell/pathology
• Fibroblasts/metabolism
• Fibroblasts/pathology
• Humans
• Patched-1 Receptor/metabolism
• Signal Transduction/physiology
• Skin Neoplasms/metabolism
• Skin Neoplasms/pathology

The temporomandibular joint (TMJ) is an intricate structure composed of the mandibular condyle, articular disc, and glenoid fossa in the temporal bone. Apical condylar cartilage is classified as a secondary cartilage, is fibrocartilaginous in nature, and is structurally distinct from growth plate and articular cartilage in long bones. Condylar cartilage is organized in distinct cellular layers that include a superficial layer that produces lubricants, a polymorphic/progenitor layer that contains stem/progenitor cells, and underlying layers of flattened and hypertrophic chondrocytes. Uniquely, progenitor cells reside near the articular surface, proliferate, undergo chondrogenesis, and mature into hypertrophic chondrocytes. During the past decades, there has been a growing interest in the molecular mechanisms by which the TMJ develops and acquires its unique structural and functional features. Indian hedgehog (Ihh), which regulates skeletal development including synovial joint formation, also plays pivotal roles in TMJ development and postnatal maintenance. This review provides a description of the many important recent advances in Hedgehog (Hh) signaling in TMJ biology. These include studies that used conventional approaches and those that analyzed the phenotype of tissue-specific mouse mutants lacking Ihh or associated molecules. The recent advances in understanding the molecular mechanism regulating TMJ development are impressive and these findings will have major implications for future translational medicine tools to repair and regenerate TMJ congenital anomalies and acquired diseases, such as degenerative damage in TMJ osteoarthritic conditions.

• Ihh
• PTHrP
• TMJ
• articular disc
• osteoarthritis
• synovial joint

Biologically active chemical compounds may provide remedies for several diseases. Meanwhile, Machine Learning techniques applied to Drug Discovery, which are cheaper and faster than wet-lab experiments, have the capability to more effectively identify molecules with the expected pharmacological activity. Therefore, it is urgent and essential to develop more representative descriptors and reliable classification methods to accurately predict molecular activity. In this paper, we investigate the potential of a novel representation based on Spherical Harmonics fed into Probabilistic Classification Vector Machines classifier, namely SHPCVM, to compound the activity prediction task. We make use of representation learning to acquire the features which describe the molecules as precise as possible. To verify the performance of SHPCVM ten-fold cross-validation tests are performed on twenty-one G protein-coupled receptors (GPCRs). Experimental outcomes (accuracy of 0.86) assessed by the classification accuracy, precision, recall, Matthews’ Correlation Coefficient and Cohen’s kappa reveal that using our Spherical Harmonics-based representation which is relatively short and Probabilistic Classification Vector Machines can achieve very satisfactory performance results for GPCRs.

• G protein-coupled receptors
• cheminformatics
• machine learning
• molecular activity predictions
• molecular representation
• representation learning

The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling.

• GLI transcription factors
• Hedgehog signaling
• Smoothened inhibitors
• cancer stem cells
• drug resistance

• CK1
• Ci
• Cul1
• Cul3
• Cul4
• GSK3
• Gli1
• Gli2
• Gli3
• Gprk2
• Grk2
• Hh
• Lysosome
• PKA
• Phosphorylation
• Proteasome
• Ptc
• Ptch1
• SUMO
• Shh
• Slimb
• Smo
• Smurf
• Sufu
• Ubiquitin
• Uchl5
• Usp8

• Hedgehog
• Smoothened
• cancer
• cholesterol
• cilia
• membrane
• oncogene
• signaling

• Glil
• Ludmila Belayev test
• Ptch1
• Smo
• TUNEL assay
• acupuncture treatment
• intracerebral hemorrhage
• nerve regeneration
• neural regeneration
• neurological function
• purmorphamine

• chorda tympani nerve
• circumvallate papilla
• fungiform papilla
• taste receptor cell
• taste regeneration

The Sonic Hedgehog (Shh) signaling pathway is active during embryonic development in metazoans, and provides instructional cues necessary for proper tissue patterning. The pathway signal transducing component, Smoothened (Smo), is a G protein-coupled receptor (GPCR) that has been demonstrated to signal through at least two effector routes. The first is a G protein–independent canonical route that signals to Gli transcriptional effectors to establish transcriptional programs specifying cell fate during early embryonic development. The second, commonly referred to as the noncanonical Smo signal, induces rapid, transcription-independent responses that are essential for establishing and maintaining distinct cell behaviors during development. Herein, we discuss contributions of this noncanonical route during embryonic development. We also highlight important open questions regarding noncanonical Smo signal route selection during development, and consider implications of noncanonical signal corruption in disease.

• Sonic Hedgehog
• development
• morphogenesis
• noncanonical signaling
• signal transduction
• smoothened

• Fibroblast growth factor 10
• Forkhead box F1
• Hedgehog signalling
• Lung branching morphogenesis
• Mouse model
• Patched1