{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:49:26Z","timestamp":1760233766338,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,16]],"date-time":"2021-02-16T00:00:00Z","timestamp":1613433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hungarian National Research, Development and Innovation Office","award":["NAP2-2017-1.2.1-NKP-0002, K129065, KNN121510 and KH130356"],"award-info":[{"award-number":["NAP2-2017-1.2.1-NKP-0002, K129065, KNN121510 and KH130356"]}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["FWF I3522, FWF I3977 and I4677"],"award-info":[{"award-number":["FWF I3522, FWF I3977 and I4677"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Thematic Excellence Program","award":["TUDFO\/51757\/2019-ITM"],"award-info":[{"award-number":["TUDFO\/51757\/2019-ITM"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Spitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sample of a 37-year-old male patient. We found that the cell line carries a rare MEK1 mutation (pGlu102_Lys104delinsGln) that belongs to the RAF- and phosphorylation-independent subgroup of MEK1 alternations supposedly insensitive to allosteric MEK inhibitors. The in vivo tumorigenicity was tested in three different models by injecting the cells subcutaneously, intravenously or into the thoracic cavity of SCID mice. In the intrapleural model, macroscopic tumors formed in the chest cavity after two months, while subcutaneously and intravenously delivered cells showed limited growth. In vitro, trametinib\u2014but not selumentinib\u2014and the ATP-competitive MEK inhibitor MAP855 strongly decreased the viability of the cells and induced cell death. In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib.<\/jats:p>","DOI":"10.3390\/cancers13040829","type":"journal-article","created":{"date-parts":[[2021,2,16]],"date-time":"2021-02-16T08:09:09Z","timestamp":1613462949000},"page":"829","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation"],"prefix":"10.3390","volume":"13","author":[{"given":"Luca","family":"Heged\u00fcs","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, University Medicine Essen\u2013Ruhrlandklinik, T\u00fcschener Weg 40, 45239 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2903-5541","authenticated-orcid":false,"given":"\u00d6zlem","family":"Okumus","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Medicine Essen\u2013Ruhrlandklinik, T\u00fcschener Weg 40, 45239 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Livingstone","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medicine Essen, Esmarchstra\u00dfe 14, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcell","family":"Baranyi","sequence":"additional","affiliation":[{"name":"2nd Department of Pathology, Semmelweis University, \u00dcll\u0151i \u00fat 93, 1091 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ildik\u00f3","family":"Kov\u00e1cs","sequence":"additional","affiliation":[{"name":"National Kor\u00e1nyi Institute of Pulmonology, Pihen\u0151 \u00fat 1, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bal\u00e1zs","family":"D\u00f6me","sequence":"additional","affiliation":[{"name":"National Kor\u00e1nyi Institute of Pulmonology, Pihen\u0151 \u00fat 1, 1122 Budapest, Hungary"},{"name":"Department of Thoracic Surgery, National Institute of Oncology, R\u00e1th Gy\u00f6rgy u. 7-9, 1122 Budapest, Hungary"},{"name":"Department of Thoracic Surgery, Medical University of Vienna, W\u00e4hringer G\u00fcrtel 18-20, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f3zsef","family":"T\u00f3v\u00e1ri","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology, National Institute of Oncology, R\u00e1th Gy\u00f6rgy u. 7-9, 1122 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1gnes","family":"B\u00e1nkfalvi","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Medicine Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Schadendorf","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medicine Essen, Esmarchstra\u00dfe 14, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7787-991X","authenticated-orcid":false,"given":"Clemens","family":"Aigner","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Medicine Essen\u2013Ruhrlandklinik, T\u00fcschener Weg 40, 45239 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4341-4153","authenticated-orcid":false,"given":"Bal\u00e1zs","family":"Heged\u00fcs","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, University Medicine Essen\u2013Ruhrlandklinik, T\u00fcschener Weg 40, 45239 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.pathol.2015.12.007","article-title":"Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy","volume":"48","author":"Wiesner","year":"2016","journal-title":"Pathology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"249","DOI":"10.21037\/atm.2018.05.23","article-title":"An update on molecular alterations in melanocytic tumors with emphasis on Spitzoid lesions","volume":"6","author":"Dimonitsas","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/s41379-019-0445-z","article-title":"Spitz melanoma is a distinct subset of spitzoid melanoma","volume":"33","author":"Raghavan","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/modpathol.2016.237","article-title":"Spitz nevi and Spitzoid melanomas: Exome sequencing and comparison with conventional melanocytic nevi and melanomas","volume":"30","author":"Lazova","year":"2017","journal-title":"Mod. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1016\/j.jid.2019.12.031","article-title":"Integrating Next-Generation Sequencing with Morphology Improves Prognostic and Biologic Classification of Spitz Neoplasms","volume":"140","author":"Quan","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"11830","DOI":"10.1038\/s41598-018-30202-5","article-title":"Intrinsically active MEK variants are differentially regulated by proteinases and phosphatases","volume":"8","author":"Ordan","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1093\/bfgp\/els022","article-title":"MEK genomics in development and disease","volume":"11","author":"Andersen","year":"2012","journal-title":"Brief. Funct. Genom."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2661","DOI":"10.1021\/bi801898e","article-title":"Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors","volume":"48","author":"Fischmann","year":"2009","journal-title":"Biochemistry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"18814","DOI":"10.1074\/jbc.C117.806067","article-title":"How activating mutations affect MEK1 regulation and function","volume":"292","author":"Jindal","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1158\/2159-8290.CD-18-1321","article-title":"Targeting Alterations in the RAF-MEK Pathway","volume":"9","author":"Yaeger","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101907","DOI":"10.1016\/j.ctrv.2019.101907","article-title":"Trametinib in the treatment of multiple malignancies harboring MEK1 mutations","volume":"81","author":"Lian","year":"2019","journal-title":"Cancer Treat. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1158\/1078-0432.CCR-14-2124","article-title":"MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking","volume":"21","author":"Arcila","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Estep, A.L., Palmer, C., McCormick, F., and Rauen, K.A. (2007). Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: Implications for therapy. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0001279"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/ng.1026","article-title":"Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma","volume":"44","author":"Nikolaev","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1158\/2159-8290.CD-17-1452","article-title":"Allele-Specific Mechanisms of Activation of MEK1 Mutants Determine Their Properties","volume":"8","author":"Gao","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s40265-018-0884-8","article-title":"BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers","volume":"78","author":"Sanchez","year":"2018","journal-title":"Drugs"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/S1470-2045(19)30277-3","article-title":"Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: A multicentre, phase 2 trial","volume":"20","author":"Fangusaro","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1158\/1535-7163.MCT-14-0832","article-title":"The Novel ATP-Competitive MEK\/Aurora Kinase Inhibitor BI-847325 Overcomes Acquired BRAF Inhibitor Resistance through Suppression of Mcl-1 and MEK Expression","volume":"14","author":"Phadke","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1158\/1535-7163.MCT-13-0667","article-title":"Novel ATP-competitive MEK inhibitor E6201 is effective against vemurafenib-resistant melanoma harboring the MEK1-C121S mutation in a preclinical model","volume":"13","author":"Narita","year":"2014","journal-title":"Mol. Cancer Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nbt.3391","article-title":"Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity","volume":"34","author":"Chang","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.jaad.2014.04.012","article-title":"Clinicopathologic features and survival in Spitzoid malignant melanoma and conventional malignant melanoma","volume":"71","author":"Semkova","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.ccell.2016.02.010","article-title":"Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2","volume":"29","author":"Foster","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Joshi, M., Rice, S.J., Liu, X., Miller, B., and Belani, C.P. (2015). Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0118210"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.radonc.2015.06.026","article-title":"Trametinib radiosensitises RAS- and BRAF-mutated melanoma by perturbing cell cycle and inducing senescence","volume":"117","author":"Schick","year":"2015","journal-title":"Radiother. Oncol."},{"key":"ref_26","first-page":"2251","article-title":"Trametinib: A MEK inhibitor for management of metastatic melanoma","volume":"8","author":"Lugowska","year":"2015","journal-title":"Onco Targets Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1158\/1535-7163.MCT-17-0196","article-title":"Ceritinib Enhances the Efficacy of Trametinib in BRAF\/NRAS-Wild-Type Melanoma Cell Lines","volume":"17","author":"Verduzco","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_28","first-page":"23","article-title":"Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1\/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo","volume":"39","author":"Yamaguchi","year":"2011","journal-title":"Int. J. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1158\/2159-8290.CD-19-0356","article-title":"V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer","volume":"9","author":"Gao","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Garay, T., Kenessey, I., Molnar, E., Juhasz, E., Reti, A., Laszlo, V., Rozsas, A., Dobos, J., Dome, B., and Berger, W. (2015). Prenylation inhibition-induced cell death in melanoma: Reduced sensitivity in BRAF mutant\/PTEN wild-type melanoma cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117021"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/4\/829\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:24:50Z","timestamp":1760160290000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/4\/829"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,16]]},"references-count":30,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["cancers13040829"],"URL":"https:\/\/doi.org\/10.3390\/cancers13040829","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2021,2,16]]}}}