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Combined activity of temozolomide and the mTOR inhibitor temsirolimus in metastatic melanoma involves DKK1
Author(s) -
Niessner Heike,
Kosnopfel Corinna,
Sinnberg Tobias,
Beck Daniela,
Krieg Kathrin,
Wanke Ines,
Lasithiotakis Konstantinos,
Bonin Michael,
Garbe Claus,
Meier Friedegund
Publication year - 2017
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.13372
Subject(s) - temsirolimus , temozolomide , dkk1 , melanoma , dacarbazine , pi3k/akt/mtor pathway , vemurafenib , cancer research , pharmacology , medicine , wnt signaling pathway , downregulation and upregulation , apoptosis , chemistry , discovery and development of mtor inhibitors , signal transduction , metastatic melanoma , biochemistry , gene , glioblastoma
The BRAFV 600E inhibitor vemurafenib achieves remarkable clinical responses in patients with BRAF ‐mutant melanoma, but its effects are limited by the onset of drug resistance. In the case of resistance, chemotherapy can still be applied as second line therapy. However, it yields low response rates and strategies are urgently needed to potentiate its effects. In a previous study, we showed that the inhibition of the PI 3K‐ AKT ‐ mTOR pathway significantly increases sensitivity of melanoma cells to chemotherapeutic drugs ( J. Invest. Dermatol . 2009 , 129 , 1500). In this study, the combination of the mTOR inhibitor temsirolimus with the chemotherapeutic agent temozolomide significantly increases growth inhibition and apoptosis in melanoma cells compared to temsirolimus or temozolomide alone. The combination of temozolomide with temsirolimus is not only effective in established but also in newly isolated and vemurafenib‐resistant metastatic melanoma cell lines. These effects are associated with the downregulation of the anti‐apoptotic protein Mcl‐1 and the upregulation of the Wnt antagonist Dickkopf homologue 1 ( DKK 1). Knock‐down of DKK 1 suppresses apoptosis induction by the combination of temsirolimus and temozolomide. These data suggest that the inhibition of the mTOR pathway increases sensitivity of melanoma cells towards temozolomide. Chemosensitisation is associated with enhanced expression of the Wnt antagonist DKK1.