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Oncotarget. 2017 Jul 11;8(28):45687-45697. doi: 10.18632/oncotarget.17669.

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

Author information

1
German Cancer Research Center, 69120 Heidelberg, Germany.
2
Current address: Department of Gastroenterology, University Hospital of Zürich, 8091 Zürich, Switzerland.
3
Department of Dermatology, Venerology and Allergology, University Medical Center Mannheim, Ruprecht Karls University of Heidelberg, 68167 Mannheim, Germany.
4
Current address: Department of Dermatology, Venerology and Allergology, General Hospital Karlsruhe, 76187 Karlsruhe, Germany.

Abstract

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.

KEYWORDS:

RAS mutation; T cell lymphoma; kinase; small molecule inhibitor; targeted therapy

PMID:
28537899
PMCID:
PMC5542218
DOI:
10.18632/oncotarget.17669
[Indexed for MEDLINE]
Free PMC Article

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