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BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1

Please always quote using this URN: urn:nbn:de:bvb:20-opus-177261
  • Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-inducedApproximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application.show moreshow less

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Metadaten
Author: Johannes Grimm, Anita Hufnagel, Marion Wobser, Andreas Borst, Sebastian Haferkamp, Roland Houben, Svenja Meierjohann
URN:urn:nbn:de:bvb:20-opus-177261
Document Type:Journal article
Faculties:Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften
Medizinische Fakultät / Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie
Language:English
Parent Title (English):Oncogenesis
Year of Completion:2018
Volume:7
Issue:71
Source:Oncogenesis (2018) 7:71. DOI: 10.1038/s41389-018-0082-2
DOI:https://doi.org/10.1038/s41389-018-0082-2
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:BRAF; melanoma; senescence; tumor
Release Date:2019/04/09
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2018
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International