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NRAS mutations in cutaneous T cell lymphoma (CTCL) sensitize tumors towards treatment with the multikinase inhibitor Sorafenib

Therapy of cutaneous T cell lymphoma (CTCL) is complicated by a distinct resistance of the malignant T cells towards apoptosis that can be caused by NRAS mutations in late-stage patients. These mutations correlate with decreased overall survival, but sensitize the respective CTCL cells towards MEK-i...

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Bibliographische Detailangaben
Hauptverfasser: Kießling, Michael (VerfasserIn) , Nicolay, Jan Peter (VerfasserIn) , Schlör, Tabea (VerfasserIn) , Klemke, Claus-Detlev (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: May 07, 2017
In: OncoTarget
Year: 2017, Jahrgang: 8, Heft: 28, Pages: 45687-45697
ISSN:1949-2553
DOI:10.18632/oncotarget.17669
Online-Zugang:Verlag, kostenfrei, Volltext: http://dx.doi.org/10.18632/oncotarget.17669
Verlag, kostenfrei, Volltext: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=17669&path[]=56573
Volltext
Verfasserangaben:Michael K. Kießling, Jan P. Nicolay, Tabea Schlör, Claus-Detlev Klemke, Dorothee Süss, Peter H. Krammer and Karsten Gülow
Beschreibung
Zusammenfassung:Therapy of cutaneous T cell lymphoma (CTCL) is complicated by a distinct resistance of the malignant T cells towards apoptosis that can be caused by NRAS mutations in late-stage patients. These mutations correlate with decreased overall survival, but sensitize the respective CTCL cells towards MEK-inhibition-induced apoptosis which represents a promising novel therapeutic target in CTCL. Here, we show that the multi-kinase inhibitor Sorafenib induces apoptosis in NRAS-mutated CTCL cells. CTCL cell lines and to a minor extent primary T cells from Sézary patients without NRAS mutations are also affected by Sorafenib-induced apoptosis suggesting a sensitizing role of NRAS mutations for Sorafenib-induced apoptosis. When combining Sorafenib with the established CTCL medication Vorinostat we detected an increase in cell death sensitivity in CTCL cells. The combination treatment acted synergistically in apoptosis induction in both non-mutant and mutant CTCL cells. Mechanistically, this synergistic apoptosis induction by Sorafenib and Vorinostat is based on the downregulation of the anti-apoptotic protein Mcl-1, but not of other Bcl-2 family members. Taken together, these findings suggest that Sorafenib in combination with Vorinostat represents a novel therapeutic approach for the treatment of CTCL patients.
Beschreibung:Gesehen am 28.05.2018
Beschreibung:Online Resource
ISSN:1949-2553
DOI:10.18632/oncotarget.17669

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