{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:03:51Z","timestamp":1790636631484,"version":"4.1.0"},"reference-count":111,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T00:00:00Z","timestamp":1664928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>The G protein-coupled receptor Smoothened (Smo) is a central signal transducer of the Hedgehog (Hh) pathway which has been linked to diverse forms of tumours. Stimulated by advancements in structural and functional characterisation, the Smo receptor has been recognised as an important therapeutic target in Hh-driven cancers, and several Smo inhibitors have now been approved for cancer therapy. This receptor is also known to be an oncoprotein itself and its gain-of-function variants have been associated with skin, brain, and liver cancers. According to the COSMIC database, oncogenic mutations of Smo have been identified in various other tumours, although their oncogenic effect remains unknown in these tissues. Drug resistance is a common challenge in cancer therapies targeting Smo, and data analysis shows that healthy individuals also harbour resistance mutations. Based on the importance of Smo in cancer progression and the high incidence of resistance towards Smo inhibitors, this review suggests that detection of Smo variants through tumour profiling could lead to increased precision and improved outcomes of anti-cancer treatments.<\/jats:p>","DOI":"10.3390\/jpm12101648","type":"journal-article","created":{"date-parts":[[2022,10,9]],"date-time":"2022-10-09T01:43:11Z","timestamp":1665279791000},"page":"1648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7318-9065","authenticated-orcid":false,"given":"Alina","family":"Nicheperovich","sequence":"first","affiliation":[{"name":"Institute of Structural and Molecular Biology, Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7250-2208","authenticated-orcid":false,"given":"Andrea","family":"Townsend-Nicholson","sequence":"additional","affiliation":[{"name":"Institute of Structural and Molecular Biology, Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nature08144","article-title":"The Structure and Function of G-Protein-Coupled Receptors","volume":"459","author":"Rosenbaum","year":"2009","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Yang, D., Zhou, Q., Labroska, V., Qin, S., Darbalaei, S., Wu, Y., Yuliantie, E., Xie, L., Tao, H., and Cheng, J. (2021). G Protein-Coupled Receptors: Structure- and Function-Based Drug Discovery. Signal Transduct. Target. Ther., 6.","DOI":"10.1038\/s41392-020-00435-w"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.tips.2014.03.002","article-title":"Targeting of Smoothened for Therapeutic Gain","volume":"35","author":"Ruat","year":"2014","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"111","DOI":"10.4161\/cbt.5.1.2379","article-title":"Hedgehog Signaling in Human Hepatocellular Carcinoma","volume":"5","author":"Patil","year":"2006","journal-title":"Cancer Biol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/nature02009","article-title":"Hedgehog Is an Early and Late Mediator of Pancreatic Cancer Tumorigenesis","volume":"425","author":"Thayer","year":"2003","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6071","DOI":"10.1158\/0008-5472.CAN-04-0416","article-title":"Hedgehog Signaling Pathway Is a New Therapeutic Target for Patients with Breast Cancer","volume":"64","author":"Kubo","year":"2004","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jdermsci.2015.02.007","article-title":"Hedgehog Signaling in Basal Cell Carcinoma","volume":"78","author":"Otsuka","year":"2015","journal-title":"J. Dermatol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1093\/carcin\/bgi292","article-title":"Dysregulation of the Hedgehog Pathway in Human Hepatocarcinogenesis","volume":"27","author":"Sicklick","year":"2006","journal-title":"Carcinogenesis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1158\/1078-0432.CCR-09-1913","article-title":"Overexpression of Smoothened Activates the Sonic Hedgehog Signaling Pathway in Pancreatic Cancer\u2013Associated Fibroblasts","volume":"16","author":"Walter","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/34201","article-title":"Activating Smoothened Mutations in Sporadic Basal-Cell Carcinoma","volume":"391","author":"Xie","year":"1998","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1111\/bjd.14425","article-title":"Segmental Basal Cell Naevus Syndrome Caused by an Activating Mutation in Smoothened","volume":"175","author":"Khamaysi","year":"2016","journal-title":"Br. J. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/ng.2526","article-title":"Genomic Sequencing of Meningiomas Identifies Oncogenic SMO and AKT1 Mutations","volume":"45","author":"Brastianos","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nature11284","article-title":"Dissecting the Genomic Complexity Underlying Medulloblastoma","volume":"488","author":"Jones","year":"2012","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jeng, K.-S., Sheen, I.-S., Leu, C.-M., Tseng, P.-H., and Chang, C.-F. (2020). The Role of Smoothened in Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186863"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D335","DOI":"10.1093\/nar\/gkaa1080","article-title":"GPCRdb in 2021: Integrating GPCR Sequence, Structure and Function","volume":"49","author":"Kooistra","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/j.1527-5299.2004.02019.x","article-title":"The Emerging Pharmacogenomics of the \u0392-Adrenergic Receptors","volume":"10","author":"Taylor","year":"2004","journal-title":"Congest. Heart Fail."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.tips.2007.09.001","article-title":"The Frizzled Family of Unconventional G-Protein-Coupled Receptors","volume":"28","author":"Schulte","year":"2007","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, X., Zhao, F., Wu, Y., Yang, J., Han, G.W., Zhao, S., Ishchenko, A., Ye, L., Lin, X., and Ding, K. (2017). Crystal Structure of a Multi-Domain Human Smoothened Receptor in Complex with a Super Stabilizing Ligand. Nat. Commun., 8.","DOI":"10.1038\/ncomms15383"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/384129a0","article-title":"The Tumour-Suppressor Gene Patched Encodes a Candidate Receptor for Sonic Hedgehog","volume":"384","author":"Stone","year":"1996","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"R437","DOI":"10.1016\/S0960-9822(02)00920-X","article-title":"Hedgehog Signalling: Pulling Apart Patched and Smoothened","volume":"12","author":"Stark","year":"2002","journal-title":"Curr. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1038\/nature00989","article-title":"Patched Acts Catalytically to Suppress the Activity of Smoothened","volume":"418","author":"Taipale","year":"2002","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/s41586-019-1355-4","article-title":"Smoothened Stimulation by Membrane Sterols Drives Hedgehog Pathway Activity","volume":"571","author":"Deshpande","year":"2019","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1038\/s41589-020-0646-2","article-title":"Sterols in an Intramolecular Channel of Smoothened Mediate Hedgehog Signaling","volume":"16","author":"Qi","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/s41586-019-1286-0","article-title":"Cryo-EM Structure of Oxysterol-Bound Human Smoothened Coupled to a Heterotrimeric Gi","volume":"571","author":"Qi","year":"2019","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nature18934","article-title":"Structural Basis of Smoothened Regulation by Its Extracellular Domains","volume":"535","author":"Byrne","year":"2016","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.cell.2016.08.003","article-title":"Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling","volume":"166","author":"Huang","year":"2016","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nature12167","article-title":"Structure of the Human Smoothened Receptor Bound to an Antitumour Agent","volume":"497","author":"Wang","year":"2013","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Wang, C., Wu, H., Evron, T., Vardy, E., Han, G.W., Huang, X.-P., Hufeisen, S.J., Mangano, T.J., Urban, D.J., and Katritch, V. (2014). Structural Basis for Smoothened Receptor Modulation and Chemoresistance to Anticancer Drugs. Nat. Commun., 5.","DOI":"10.1038\/ncomms5355"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Weierstall, U., James, D., Wang, C., White, T.A., Wang, D., Liu, W., Spence, J.C.H., Bruce Doak, R., Nelson, G., and Fromme, P. (2014). Lipidic Cubic Phase Injector Facilitates Membrane Protein Serial Femtosecond Crystallography. Nat. Commun., 5.","DOI":"10.1038\/ncomms4309"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wright, S.C., Kozielewicz, P., Kowalski-Jahn, M., Petersen, J., Bowin, C.-F., Slodkowicz, G., Marti-Solano, M., Rodr\u00edguez, D., Hot, B., and Okashah, N. (2019). A Conserved Molecular Switch in Class F Receptors Regulates Receptor Activation and Pathway Selection. Nat. Commun., 10.","DOI":"10.1038\/s41467-019-08630-2"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1146\/annurev-biochem-060614-033910","article-title":"The Molecular Basis of G Protein\u2013Coupled Receptor Activation","volume":"87","author":"Weis","year":"2018","journal-title":"Annu. Rev. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.1242\/dev.083691","article-title":"Roles for Hedgehog Signaling in Adult Organ Homeostasis and Repair","volume":"141","author":"Petrova","year":"2014","journal-title":"Development"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17905","DOI":"10.1074\/jbc.R112.356006","article-title":"Hedgehog Secretion and Signal Transduction in Vertebrates","volume":"287","author":"Ryan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Robbins, D.J., Fei, D.L., and Riobo, N.A. (2012). The Hedgehog Signal Transduction Network. Sci. Signal., 5.","DOI":"10.1126\/scisignal.2002906"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Chen, Y., Sasai, N., Ma, G., Yue, T., Jia, J., Briscoe, J., and Jiang, J. (2011). Sonic Hedgehog Dependent Phosphorylation by CK1\u03b1 and GRK2 Is Required for Ciliary Accumulation and Activation of Smoothened. PLoS Biol., 9.","DOI":"10.1371\/journal.pbio.1001083"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wilson, C.W., Chen, M.-H., and Chuang, P.-T. (2009). Smoothened Adopts Multiple Active and Inactive Conformations Capable of Trafficking to the Primary Cilium. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005182"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1038\/nature04117","article-title":"Vertebrate Smoothened Functions at the Primary Cilium","volume":"437","author":"Corbit","year":"2005","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1038\/cr.2012.134","article-title":"Smoothened Transduces Hedgehog Signal by Forming a Complex with Evc\/Evc2","volume":"22","author":"Yang","year":"2012","journal-title":"Cell Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1083\/jcb.201004108","article-title":"A Mechanism for Vertebrate Hedgehog Signaling: Recruitment to Cilia and Dissociation of SuFu\u2013Gli Protein Complexes","volume":"191","author":"Tukachinsky","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Akhshi, T., and Trimble, W.S. (2021). A Non-Canonical Hedgehog Pathway Initiates Ciliogenesis and Autophagy. J. Cell Biol., 220.","DOI":"10.1083\/jcb.202004179"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4482","DOI":"10.1073\/pnas.1018217108","article-title":"Sonic Hedgehog Signaling Is Decoded by Calcium Spike Activity in the Developing Spinal Cord","volume":"108","author":"Belgacem","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.cell.2012.09.021","article-title":"Hedgehog Partial Agonism Drives Warburg-like Metabolism in Muscle and Brown Fat","volume":"151","author":"Teperino","year":"2012","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"19589","DOI":"10.1074\/jbc.M110.197111","article-title":"Heterotrimeric Gi Proteins Link Hedgehog Signaling to Activation of Rho Small GTPases to Promote Fibroblast Migration","volume":"286","author":"Polizio","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"570","DOI":"10.4161\/cc.9.3.10591","article-title":"Hedgehog Proteins Activate Pro-Angiogenic Responses in Endothelial Cells through Non-Canonical Signaling Pathways","volume":"9","author":"Chinchilla","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3623","DOI":"10.1158\/0008-5472.CAN-14-2999-T","article-title":"RAS\/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway\u2013Dependent Tumors","volume":"75","author":"Zhao","year":"2015","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Buonamici, S., Williams, J., Morrissey, M., Wang, A., Guo, R., Vattay, A., Hsiao, K., Yuan, J., Green, J., and Ospina, B. (2010). Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma. Sci. Transl. Med., 2.","DOI":"10.1126\/scitranslmed.3001599"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4718","DOI":"10.1182\/blood-2012-12-470153","article-title":"Trimeric G Protein-CARMA1 Axis Links Smoothened, the Hedgehog Receptor Transducer, to NF-\u039aB Activation in Diffuse Large B-Cell Lymphoma","volume":"121","author":"Qu","year":"2013","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nri.2017.142","article-title":"NF-\u039aB, Inflammation, Immunity and Cancer: Coming of Age","volume":"18","author":"Taniguchi","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.devcel.2016.09.014","article-title":"Regulation of Smoothened Trafficking and Hedgehog Signaling by the SUMO Pathway","volume":"39","author":"Ma","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"12605","DOI":"10.1074\/jbc.M112.399477","article-title":"Smoothened Oligomerization\/Higher Order Clustering in Lipid Rafts Is Essential for High Hedgehog Activity Transduction","volume":"288","author":"Shi","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"21723","DOI":"10.1073\/pnas.2003787117","article-title":"Agonist-Induced Formation of Unproductive Receptor-G 12 Complexes","volume":"117","author":"Okashah","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1126\/science.1104135","article-title":"Activity-Dependent Internalization of Smoothened Mediated by \u00df-Arrestin 2 and GRK2","volume":"306","author":"Chen","year":"2004","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Marada, S., Navarro, G., Truong, A., Stewart, D.P., Arensdorf, A.M., Nachtergaele, S., Angelats, E., Opferman, J.T., Rohatgi, R., and McCormick, P.J. (2015). Functional Divergence in the Role of N-Linked Glycosylation in Smoothened Signaling. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005473"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/jnc.15337","article-title":"N-glycosylation of the Human Neuropeptide QRFP Receptor (QRFPR) Is Essential for Ligand Binding and Receptor Activation","volume":"158","author":"Wang","year":"2021","journal-title":"J. Neurochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1016\/j.jmb.2020.01.028","article-title":"Calcitonin Receptor N-Glycosylation Enhances Peptide Hormone Affinity by Controlling Receptor Dynamics","volume":"432","author":"Lee","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Desai, P.B., Stuck, M.W., Lv, B., and Pazour, G.J. (2020). Ubiquitin Links Smoothened to Intraflagellar Transport to Regulate Hedgehog Signaling. J. Cell Biol., 219.","DOI":"10.1083\/jcb.201912104"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.molcel.2017.02.015","article-title":"Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling","volume":"66","author":"Xiao","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41422-022-00622-0","article-title":"Cholesterylation of Smoothened Is a Calcium-Accelerated Autoreaction Involving an Intramolecular Ester Intermediate","volume":"32","author":"Hu","year":"2022","journal-title":"Cell Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/nchembio.765","article-title":"Oxysterols Are Allosteric Activators of the Oncoprotein Smoothened","volume":"8","author":"Nachtergaele","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nchembio.1290","article-title":"Oxysterol Binding to the Extracellular Domain of Smoothened in Hedgehog Signaling","volume":"9","author":"Nedelcu","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.devcel.2013.07.015","article-title":"Hedgehog Pathway Modulation by Multiple Lipid Binding Sites on the Smoothened Effector of Signal Response","volume":"26","author":"Myers","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.1242\/dev.125.18.3553","article-title":"The Teratogenic Veratrum Alkaloid Cyclopamine Inhibits Sonic Hedgehog Signal Transduction","volume":"125","author":"Incardona","year":"1998","journal-title":"Development"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2018.04.029","article-title":"Structural Basis of Smoothened Activation in Hedgehog Signaling","volume":"174","author":"Huang","year":"2018","journal-title":"Cell"},{"key":"ref_64","unstructured":"Tanaka, H., Nakamura, M., Kameda, C., Kubo, M., Sato, N., Kuroki, S., Tanaka, T., and Katano, M. (2009). The Hedgehog Signaling Pathway Plays an Essential Role in Maintaining the CD44+CD24-\/low Subpopulation and the Side Population of Breast Cancer Cells. Anticancer Res., 29."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.arcmed.2010.06.003","article-title":"Expression of Sonic Hedgehog Signaling Components in Hepatocellular Carcinoma and Cyclopamine-Induced Apoptosis Through Bcl-2 Downregulation In Vitro","volume":"41","author":"Chen","year":"2010","journal-title":"Arch. Med. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/417299a","article-title":"Hedgehog Regulates Cell Growth and Proliferation by Inducing Cyclin D and Cyclin, E","volume":"417","author":"Weng","year":"2002","journal-title":"Nature"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"347","DOI":"10.2353\/ajpath.2007.060066","article-title":"Hedgehog Signaling Promotes Medulloblastoma Survival via BclII","volume":"170","author":"Bar","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1038\/89083","article-title":"The Morphogen Sonic Hedgehog Is an Indirect Angiogenic Agent Upregulating Two Families of Angiogenic Growth Factors","volume":"7","author":"Pola","year":"2001","journal-title":"Nat. Med."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Chen, M., Qian, Y., Dai, J., and Chu, R. (2014). The Sonic Hedgehog Signaling Pathway Induces Myopic Development by Activating Matrix Metalloproteinase (MMP)-2 in Guinea Pigs. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096952"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1158\/0008-5472.CAN-06-3281","article-title":"Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers","volume":"67","author":"Feldmann","year":"2007","journal-title":"Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Mazumdar, T., Sandhu, R., Qadan, M., DeVecchio, J., Magloire, V., Agyeman, A., Li, B., and Houghton, J.A. (2013). Hedgehog Signaling Regulates Telomerase Reverse Transcriptase in Human Cancer Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075253"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1038\/onc.2013.212","article-title":"Evasion of P53 and G2\/M Checkpoints Are Characteristic of Hh-Driven Basal Cell Carcinoma","volume":"33","author":"Li","year":"2014","journal-title":"Oncogene"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1083\/jcb.200804042","article-title":"Sonic Hedgehog Signaling Impairs Ionizing Radiation\u2013Induced Checkpoint Activation and Induces Genomic Instability","volume":"183","author":"Leonard","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/s41375-019-0641-3","article-title":"Elevated Hedgehog Activity Contributes to Attenuated DNA Damage Responses in Aged Hematopoietic Cells","volume":"34","author":"Scheffold","year":"2020","journal-title":"Leukemia"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1158\/1078-0432.CCR-14-2110","article-title":"Hedgehog Pathway Inhibitors Promote Adaptive Immune Responses in Basal Cell Carcinoma","volume":"21","author":"Otsuka","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.jcmgh.2017.01.004","article-title":"Hedgehog Signaling Links Chronic Inflammation to Gastric Cancer Precursor Lesions","volume":"3","author":"Merchant","year":"2017","journal-title":"Cell. Mol. Gastroenterol. Hepatol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The Next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.tips.2009.03.007","article-title":"Mechanisms of Hedgehog Pathway Activation in Cancer and Implications for Therapy","volume":"30","author":"Scales","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1056\/NEJMoa1113538","article-title":"Inhibiting the Hedgehog Pathway in Patients with the Basal-Cell Nevus Syndrome","volume":"366","author":"Tang","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1200\/JCO.2014.60.1591","article-title":"Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog\u2013Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032","volume":"33","author":"Robinson","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1016\/j.tranon.2019.07.004","article-title":"Hedgehog Signaling: An Achilles\u2019 Heel in Cancer","volume":"12","author":"Niyaz","year":"2019","journal-title":"Transl. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1007\/s10637-018-0614-9","article-title":"A Phase Ib Study of Sonidegib (LDE225), an Oral Small Molecule Inhibitor of Smoothened or Hedgehog Pathway, in Combination with Docetaxel in Triple Negative Advanced Breast Cancer Patients: GEICAM\/2012\u201312 (EDALINE) Study","volume":"37","author":"Jimenez","year":"2019","journal-title":"Investig. New Drugs"},{"key":"ref_83","unstructured":"(2019). Sonidegib and Pembrolizumab in Treating Patients With Advanced Solid Tumors (Standard No. NCT04007744)."},{"key":"ref_84","unstructured":"(2018). Molecular Profiling of Advanced Soft-Tissue Sarcomas (MULTISARC) (Standard No. NCT03784014)."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cell.2017.11.033","article-title":"Pharmacogenomics of GPCR Drug Targets","volume":"172","author":"Hauser","year":"2018","journal-title":"Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/nrd.2017.178","article-title":"Trends in GPCR Drug Discovery: New Agents, Targets and Indications","volume":"16","author":"Hauser","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"D941","DOI":"10.1093\/nar\/gky1015","article-title":"COSMIC: The Catalogue Of Somatic Mutations In Cancer","volume":"47","author":"Tate","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/ng0996-78","article-title":"The Role of the Human Homologue of Drosophila Patched in Sporadic Basal Cell Carcinomas","volume":"14","author":"Gailani","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1007\/s11999-008-0332-2","article-title":"PATCHED-ONE or SMOOTHENED Gene Mutations Are Infrequent in Chondrosarcoma","volume":"466","author":"Yan","year":"2008","journal-title":"Clin. Orthop."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Wang, X.-D., Inzunza, H., Chang, H., Qi, Z., Hu, B., Malone, D., and Cogswell, J. (2013). Mutations in the Hedgehog Pathway Genes SMO and PTCH1 in Human Gastric Tumors. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054415"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/sj.onc.1202360","article-title":"A Frequent Activated Smoothened Mutation in Sporadic Basal Cell Carcinomas","volume":"18","author":"Lam","year":"1999","journal-title":"Oncogene"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Ighilahriz, M., Nikolaev, S., Yurchenko, A., Battistella, M., Mourah, S., Jouenne, F., Bourrat, E., and Basset-Seguin, N. (2021). A Novel Case of Gorlin Syndrome Mosaicism Involving an SMO Gene Mutation: Clinical, Histological and Molecular Analysis of Basaloid Tumours. Acta Derm. Venereol., 101.","DOI":"10.2340\/00015555-3797"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.ccell.2015.02.002","article-title":"Smoothened Variants Explain the Majority of Drug Resistance in Basal Cell Carcinoma","volume":"27","author":"Atwood","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/j.ccell.2015.02.001","article-title":"Genomic Analysis of Smoothened Inhibitor Resistance in Basal Cell Carcinoma","volume":"27","author":"Sharpe","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4104","DOI":"10.1128\/MCB.00862-12","article-title":"A Distinct Smoothened Mutation Causes Severe Cerebellar Developmental Defects and Medulloblastoma in a Novel Transgenic Mouse Model","volume":"32","author":"Dey","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/nature22973","article-title":"The Whole-Genome Landscape of Medulloblastoma Subtypes","volume":"547","author":"Northcott","year":"2017","journal-title":"Nature"},{"key":"ref_97","first-page":"345","article-title":"SMO Mutation Status Defines a Distinct and Frequent Molecular Subgroup in Olfactory Groove Meningiomas","volume":"19","author":"Boetto","year":"2017","journal-title":"Neuro-Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1080\/14656566.2020.1713094","article-title":"An Evaluation of Glasdegib for the Treatment of Acute Myelogenous Leukemia","volume":"21","author":"Thomas","year":"2020","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Chang, A.L.S., Arron, S.T., Migden, M.R., Solomon, J.A., Yoo, S., Day, B.-M., McKenna, E.F., and Sekulic, A. (2016). Safety and Efficacy of Vismodegib in Patients with Basal Cell Carcinoma Nevus Syndrome: Pooled Analysis of Two Trials. Orphanet J. Rare Dis., 11.","DOI":"10.1186\/s13023-016-0506-z"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1056\/NEJMoa1113713","article-title":"Efficacy and Safety of Vismodegib in Advanced Basal-Cell Carcinoma","volume":"366","author":"Sekulic","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Chang, A.L.S., and Oro, A.E. (2012). Initial Assessment of Tumor Regrowth After Vismodegib in Advanced Basal Cell Carcinoma. Arch. Dermatol., 148.","DOI":"10.1001\/archdermatol.2012.2354"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1126\/science.1179386","article-title":"Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma","volume":"326","author":"Yauch","year":"2009","journal-title":"Science"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.molonc.2014.09.003","article-title":"Smoothened (SMO) Receptor Mutations Dictate Resistance to Vismodegib in Basal Cell Carcinoma","volume":"9","author":"Pricl","year":"2015","journal-title":"Mol. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1158\/1078-0432.CCR-15-1588","article-title":"An Investigator-Initiated Open-Label Trial of Sonidegib in Advanced Basal Cell Carcinoma Patients Resistant to Vismodegib","volume":"22","author":"Danial","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.ccr.2014.02.004","article-title":"Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition","volume":"25","author":"Kool","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_106","unstructured":"(2020). ProTarget-A Danish Nationwide Clinical Trial on Targeted Cancer Treatment Based on Genomic Profiling (ProTarget) (Standard No. NCT04341181)."},{"key":"ref_107","unstructured":"(2021). The Finnish National Study to Facilitate Patient Access to Targeted Anti-Cancer Drugs (FINPROVE) (Standard No. NCT05159245)."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2855","DOI":"10.4155\/fmc-2018-0200","article-title":"Overcoming the Emerging Drug Resistance of Smoothened: An Overview of Small-Molecule SMO Antagonists with Antiresistance Activity","volume":"10","author":"Zhang","year":"2018","journal-title":"Future Med. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Fan, C.-W., Yarravarapu, N., Shi, H., Kulak, O., Kim, J., Chen, C., and Lum, L. (2018). A Synthetic Combinatorial Approach to Disabling Deviant Hedgehog Signaling. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-19408-9"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Pusapati, G.V., Kong, J.H., Patel, B.B., Gouti, M., Sagner, A., Sircar, R., Luchetti, G., Ingham, P.W., Briscoe, J., and Rohatgi, R. (2018). G Protein\u2013Coupled Receptors Control the Sensitivity of Cells to the Morphogen Sonic Hedgehog. Sci. Signal., 11.","DOI":"10.1126\/scisignal.aao5749"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.sbi.2019.04.007","article-title":"Structural Bioinformatics Analysis of Variants on GPCR Function","volume":"55","author":"Ranganathan","year":"2019","journal-title":"Curr. Opin. Struct. Biol."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/10\/1648\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:46:37Z","timestamp":1760143597000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/10\/1648"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,5]]},"references-count":111,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["jpm12101648"],"URL":"https:\/\/doi.org\/10.3390\/jpm12101648","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202209.0205.v1","asserted-by":"object"}]},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,5]]}}}