Zhu, Guannan and Yi, Xiuli and Haferkamp, Sebastian and Hesbacher, Sonja and Li, Chunying and Goebeler, Matthias and Gao, Tianwen and Houben, Roland and Schrama, David (2016) Combination with gamma-secretase inhibitor prolongs treatment efficacy of BRAF inhibitor in BRAF-mutated melanoma cells. CANCER LETTERS, 376 (1). pp. 43-52. ISSN 0304-3835, 1872-7980
Full text not available from this repository. (Request a copy)Abstract
Oncogenic triggering of the MAPK pathway in melanocytes results in senescence, and senescence escape is considered as one critical step for melanocytic transformation. In melanoma, induction of a senescent like state by BRAF-inhibitors (BRAFi) in a fraction of treated cells - instead of killing - contributes to the repression of tumor growth, but may also provide a source for relapse. Here, we demonstrate that NOTCH activation in melanocytes is not only growth-promoting but it also protects these cells against oncogene-induced senescence. In turn, treatment of melanoma cells with an inhibitor of the NOTCH-activating enzyme gamma-secretase led to induction of a senescent-like status in a fraction of the cells but overall achieved only a moderate inhibition of melanoma cell growth. However, combination of gamma-secretase inhibitor (GSI) with BRAFi markedly increased the treatment efficacy particularly in long-term culture. Moreover, even melanoma cells starting to regrow after continuous BRAFi treatment - the major problem of BRAFi therapy in patients - can still be affected by the combination treatment. Thus, combining GSI with BRAFi increases the therapeutic efficacy by, at least partially, prolonging the senescent-like state of treated cells. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ONCOGENE-INDUCED SENESCENCE; N-CADHERIN; METASTATIC MELANOMA; MALIGNANT-MELANOMA; PRECURSOR LESIONS; TUMOR-SUPPRESSOR; MELANOCYTIC NEVI; NOTCH; MUTATIONS; PATHWAY; Melanoma; Notch; Senescence; BRAF inhibition |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Apr 2019 08:53 |
| Last Modified: | 08 Apr 2019 08:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3743 |
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