Combined activity of temozolomide and the mTOR inhibitor temsirolimus in metastatic melanoma involves DKK1.
The BRAFV600E 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 PI3K-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 (DKK1). Knock-down of DKK1 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.
['Niessner|Heike|H|0000-0002-2542-7022', 'Kosnopfel|Corinna|C|', 'Sinnberg|Tobias|T|', 'Beck|Daniela|D|', 'Krieg|Kathrin|K|', 'Wanke|Ines|I|', 'Lasithiotakis|Konstantinos|K|', 'Bonin|Michael|M|', 'Garbe|Claus|C|', 'Meier|Friedegund|F|']
D018906:Antineoplastic Agents, Alkylating D000971:Antineoplastic Combined Chemotherapy Protocols D017209:Apoptosis D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D003606:Dacarbazine D051766:Early Growth Response Protein 1 D020869:Gene Expression Profiling D015972:Gene Expression Regulation, Neoplastic D018014:Gene Transfer Techniques D006801:Humans D007211:Indoles D036341:Intercellular Signaling Peptides and Proteins D016086:Lentivirus D008545:Melanoma D008565:Membrane Proteins D020411:Oligonucleotide Array Sequence Analysis D015398:Signal Transduction D020123:Sirolimus D012867:Skin D012878:Skin Neoplasms D013449:Sulfonamides D058570:TOR Serine-Threonine Kinases D000077204:Temozolomide D000077484:Vemurafenib
chemotherapy PI3K-AKT-mTOR pathway Dickkopf-1 targeted therapy