Combined activity of temozolomide and the mTOR inhibitor temsirolimus in metastatic melanoma involves DKK1

Abstract

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 (1).

In the current 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 down-regulation of the antiapoptotic protein Mcl-1 and the up-regulation of the Wnt antagonist Dickkopf homolog 1 (DKK1). Knockdown 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. Chemosensitization is associated with enhanced expression of the Wnt antagonist DKK1.

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