{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T03:51:03Z","timestamp":1792900263099,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T00:00:00Z","timestamp":1703808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CIHR"},{"name":"CCSRI"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Targeted therapy resistance frequently develops in melanoma due to intratumor heterogeneity and epigenetic reprogramming. This also typically induces cross-resistance to immunotherapies. Whether this includes additional modes of therapy has not been fully assessed. We show that co-treatments of MAPKi with VSV-based oncolytics do not function in a synergistic fashion; rather, the MAPKis block infection. Melanoma resistance to vemurafenib further perturbs the cells\u2019 ability to be infected by oncolytic viruses. Resistance to vemurafenib can be induced by the loss of SOX10, a common proliferative marker in melanoma. The loss of SOX10 promotes a cross-resistant state by further inhibiting viral infection and replication. Analysis of RNA-seq datasets revealed an upregulation of interferon-stimulated genes (ISGs) in SOX10 knockout populations and targeted therapy-resistant cells. Interestingly, the induction of ISGs appears to be independent of type I IFN production. Overall, our data suggest that the pathway mediating oncolytic resistance is due to the loss of SOX10 during acquired drug resistance in melanoma.<\/jats:p>","DOI":"10.3390\/cells13010073","type":"journal-article","created":{"date-parts":[[2023,12,29]],"date-time":"2023-12-29T06:56:57Z","timestamp":1703833017000},"page":"73","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Sox10-Deficient Drug-Resistant Melanoma Cells Are Refractory to Oncolytic RNA Viruses"],"prefix":"10.3390","volume":"13","author":[{"given":"John","family":"Abou-Hamad","sequence":"first","affiliation":[{"name":"Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada"},{"name":"Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan J.","family":"Hodgins","sequence":"additional","affiliation":[{"name":"Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada"},{"name":"Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Yakubovich","sequence":"additional","affiliation":[{"name":"Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada"},{"name":"Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7644-7189","authenticated-orcid":false,"given":"Barbara C.","family":"Vanderhyden","sequence":"additional","affiliation":[{"name":"Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada"},{"name":"Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4114-0985","authenticated-orcid":false,"given":"Michele","family":"Ardolino","sequence":"additional","affiliation":[{"name":"Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada"},{"name":"Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc A.","family":"Sabourin","sequence":"additional","affiliation":[{"name":"Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada"},{"name":"Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5518","DOI":"10.1158\/0008-5472.CAN-10-0646","article-title":"RG7204 (PLX4032), a Selective BRAFV600E Inhibitor, Displays Potent Antitumor Activity in Preclinical Melanoma Models","volume":"70","author":"Yang","year":"2010","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1056\/NEJMoa1002011","article-title":"Inhibition of Mutated, Activated BRAF in Metastatic Melanoma","volume":"363","author":"Flaherty","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1056\/NEJMoa1103782","article-title":"Improved survival with vemurafenib in melanoma with BRAF V600E mutation","volume":"364","author":"Chapman","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1056\/NEJMoa1112302","article-title":"Survival in BRAF V600\u2013Mutant Advanced Melanoma Treated with Vemurafenib","volume":"366","author":"Sosman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9013","DOI":"10.1200\/jco.2013.31.15_suppl.9013","article-title":"An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM)","volume":"31","author":"Hauschild","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1056\/NEJMoa1406037","article-title":"Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma","volume":"371","author":"Long","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1056\/NEJMoa1408868","article-title":"Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma","volume":"371","author":"Larkin","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1056\/NEJMoa1412690","article-title":"Improved overall survival in melanoma with combined dabrafenib and trametinib","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature22794","article-title":"Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance","volume":"546","author":"Shaffer","year":"2017","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Giunta, E.F., Arrichiello, G., Curvietto, M., Pappalardo, A., Bosso, D., Rosanova, M., Diana, A., Giordano, P., Petrillo, A., and Federico, P. (2021). Epigenetic Regulation in Melanoma: Facts and Hopes. Cells, 10.","DOI":"10.3390\/cells10082048"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1038\/jid.2014.128","article-title":"SOX10 Promotes Melanoma Cell Invasion by Regulating Melanoma Inhibitory Activity","volume":"134","author":"Graf","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/nature13121","article-title":"Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma","volume":"508","author":"Sun","year":"2014","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"aad2197","DOI":"10.1126\/science.aad2197","article-title":"A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation","volume":"351","author":"Kaufman","year":"2016","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41467-017-02354-x","article-title":"ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma","volume":"9","author":"Han","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1038\/s41467-022-28801-y","article-title":"Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma","volume":"13","author":"Capparelli","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"105524","DOI":"10.1016\/j.isci.2022.105524","article-title":"CEACAM1 is a direct SOX10 target and inhibits melanoma immune infiltration and stemness","volume":"25","author":"Hodgins","year":"2022","journal-title":"iScience"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5416923","DOI":"10.1155\/2018\/5416923","article-title":"Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment","volume":"2018","author":"Phi","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Makena, M.R., Ranjan, A., Thirumala, V., and Reddy, A.P. (2018). Cancer stem cells: Road to therapeutic resistance and strategies to overcome resistance. Biochim. Et Biophys. Acta (BBA) Mol. Basis Dis., 1866.","DOI":"10.1016\/j.bbadis.2018.11.015"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"63","DOI":"10.31083\/j.fbl2702063","article-title":"Oncolytic viruses in melanoma","volume":"27","author":"Robinson","year":"2022","journal-title":"Front. Biosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.surg.2012.09.003","article-title":"Variation in susceptibility of human malignant melanomas to oncolytic vesicular stomatitis virus","volume":"153","author":"Blackham","year":"2012","journal-title":"Surgery"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6711","DOI":"10.1128\/JVI.00709-15","article-title":"Lassa-Vesicular Stomatitis Chimeric Virus Safely Destroys Brain Tumors","volume":"89","author":"Wollmann","year":"2015","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kimpel, J., Urbiola, C., Koske, I., Tober, R., Banki, Z., Wollmann, G., and Von Laer, D. (2018). The Oncolytic Virus VSV-GP Is Effective against Malignant Melanoma. Viruses, 10.","DOI":"10.3390\/v10030108"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/nri888","article-title":"Viruses and interferon: A fight for supremacy","volume":"2","author":"Katze","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1146\/annurev-immunol-032713-120231","article-title":"Interferon-Stimulated Genes: A Complex Web of Host Defenses","volume":"32","author":"Schneider","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e2008","DOI":"10.1002\/rmv.2008","article-title":"Defects in interferon pathways as potential biomarkers of sensitivity to oncolytic viruses","volume":"28","author":"Matveeva","year":"2018","journal-title":"Rev. Med. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nbt.3519","article-title":"Near-optimal probabilistic RNA-seq quantification","volume":"34","author":"Bray","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e90","DOI":"10.1002\/cpz1.90","article-title":"Gene Set Knowledge Discovery with Enrichr","volume":"1","author":"Xie","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S1535-6108(03)00241-1","article-title":"VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents","volume":"4","author":"Stojdl","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_32","first-page":"e920957-1","article-title":"A Review of the Molecular Pathways Involved in Resistance to BRAF Inhibitors in Patients with Advanced-Stage Melanoma","volume":"26","author":"Tian","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Tangella, L.P., Clark, M.E., and Gray, E.S. (2020). Resistance mechanisms to targeted therapy in BRAF-mutant melanoma\u2014A mini review. Biochim. Et Biophys. Acta (BBA) Gen. Subj., 1865.","DOI":"10.1016\/j.bbagen.2020.129736"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6131","DOI":"10.1158\/0008-5472.CAN-21-2078","article-title":"SOX10 Regulates Melanoma Immunogenicity through an IRF4\u2013IRF1 Axis","volume":"81","author":"Yokoyama","year":"2021","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"609","DOI":"10.3389\/fimmu.2016.00609","article-title":"Type-I Interferon Responses: From Friend to Foe in the Battle against Chronic Viral Infection","volume":"7","author":"Murira","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-Herranz, M., Taylor, J., and Sloan, R.D. (2022). IFITM proteins: Understanding their diverse roles in viral infection, cancer, and immunity. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2022.102741"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s40588-020-00150-8","article-title":"TRIM Proteins in Host Defense and Viral Pathogenesis","volume":"7","author":"Giraldo","year":"2020","journal-title":"Curr. Clin. Microbiol. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6683","DOI":"10.1038\/ncomms7683","article-title":"Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state","volume":"6","author":"Verfaillie","year":"2015","journal-title":"Nat. Commun."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/1\/73\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:43:57Z","timestamp":1760132637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/1\/73"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,29]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["cells13010073"],"URL":"https:\/\/doi.org\/10.3390\/cells13010073","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,29]]}}}