Editors' ChoiceCancer

Repurposing an HIV drug for melanoma

Sci. Signal.  12 Apr 2016:
Vol. 9, Issue 423, pp. ec85
DOI: 10.1126/scisignal.aaf8440

Inhibitors of the kinases BRAF or MEK (BRAF/MEK) can reduce tumor growth in some patients with melanoma, but resistance often develops. Microphthalmia-associated transcription factor (MITF) is implicated in promoting melanoma development. Smith et al. found that long-term treatment of cell cultures and mice bearing xenografts with BRAF/MEK inhibitors increased the abundance of MITF and its transcription factor PAX3 and that silencing MITF sensitized drug-resistant melanoma cells to the inhibitors. In a screen for small molecules that could reduce the abundance of MITF or PAX3, the most effective drug was nelfinavir mesylate, a protease inhibitor currently used to treat human immunodeficiency virus (HIV) infection. Nelfinavir sensitized melanoma cells to BRAF/MEK inhibitors but not in the context of ectopic overexpression of PAX3 or MITF. PAX3 abundance is suppressed by the transcriptional repressor SKI, which functions in complex with the transforming growth factor–β (TGF-β) effectors SMAD2 and SMAD4. BRAF/MEK inhibitors decreased the amount of SKI at the PAX3 promoter. Nelfinavir increased the amount of total as well as nuclear, phosphorylated (activated) SMAD2, the amount of SMAD2/SMAD4/SKI complexes, and the amount of SKI bound to the PAX3 promoter and consequently reduced the abundance of PAX3 and MITF. Nelfinavir could not reduce MITF abundance in the absence of SMAD4. The findings indicate that by counteracting the effects of BRAF/MEK inhibitors on SMAD2/SMAD4/SKI transrepression of PAX3, nelfinavir may be able to prevent drug resistance in melanoma; however, it is not yet clear through which proteases nelfinavir mediates these effects on SMAD2 and SKI. Furthermore, because MITF suppression is conversely associated with metastatic disease, the immediate clinical application of nelfinavir for melanoma patients is cautioned against (see Kim and Ronai). With further investigation, the findings of Smith et al. suggest that patients might be selected for nelfinavir-based therapy based on early-stage disease and tumor cell markers, such as the abundances of SMAD2, SMAD4, and SKI.

M. P. Smith, H. Brunton, E. J. Rowling, J. Ferguson, I. Arozarena, Z. Miskolczi, J. L. Lee, M. R. Girotti, R. Marais, M. P. Levesque, R. Dummer, D. T. Frederick, K. T. Flaherty, Z. A. Cooper, J. A. Wargo, C. Wellbrock, Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 29, 270–284 (2016). [PubMed]

H. Kim, Z. A. Ronai, HIV drug to aid melanoma therapies? Cancer Cell 29, 245–246 (2016). [PubMed]

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