{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T22:51:48Z","timestamp":1789167108970,"version":"build-2803163510"},"reference-count":59,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T00:00:00Z","timestamp":1567036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008730","name":"Kreftforeningen","doi-asserted-by":"publisher","award":["182716, 5745046"],"award-info":[{"award-number":["182716, 5745046"]}],"id":[{"id":"10.13039\/100008730","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004257","name":"Helse Vest","doi-asserted-by":"publisher","award":["911990"],"award-info":[{"award-number":["911990"]}],"id":[{"id":"10.13039\/501100004257","id-type":"DOI","asserted-by":"publisher"}]},{"name":"KG Jebsen","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1\/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD\/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.<\/jats:p>","DOI":"10.3390\/ijms20174235","type":"journal-article","created":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T11:26:22Z","timestamp":1567077982000},"page":"4235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7557-3784","authenticated-orcid":false,"given":"Synn\u00f8ve","family":"Nymark Aasen","sequence":"first","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"},{"name":"Department of Oncology and Medical Physics, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7185-0844","authenticated-orcid":false,"given":"Himalaya","family":"Parajuli","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuyen","family":"Hoang","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7543-6122","authenticated-orcid":false,"given":"Zichao","family":"Feng","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"},{"name":"Brain Science Research Institute, Shandong University, 44 Wenhuaxi Road, Jinan 250100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krister","family":"Stokke","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"},{"name":"Brain Science Research Institute, Shandong University, 44 Wenhuaxi Road, Jinan 250100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kislay","family":"Roy","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Bjerkvig","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"},{"name":"NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84 Val Fleuri, 1526 Luxembourg, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stian","family":"Knappskog","sequence":"additional","affiliation":[{"name":"Department of Oncology and Medical Physics, Haukeland University Hospital, Jonas Lies vei 65, 5021 Bergen, Norway"},{"name":"Section of Oncology, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits","family":"Thorsen","sequence":"additional","affiliation":[{"name":"Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"},{"name":"NorLux Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, 84 Val Fleuri, 1526 Luxembourg, Luxembourg"},{"name":"The Molecular Imaging Center, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1046\/j.1365-2230.2000.00693.x","article-title":"Epidemiology of melanoma","volume":"25","author":"Marks","year":"2000","journal-title":"Clin. 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