Editors' ChoiceCancer

Intercepting reversible drug tolerance to improve targeted therapy

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Science Translational Medicine  30 Mar 2016:
Vol. 8, Issue 332, pp. 332ec52
DOI: 10.1126/scitranslmed.aaf6467

Patients who stop responding to targeted therapies often have tumors with extensive genomic heterogeneity that can give rise to multiple, complex resistance mechanisms. Reversing established resistance is therefore challenging; thus, new therapeutic strategies are instead seeking to suppress resistance before it emerges. To explore resistance-prevention strategies in the context of BRAF mutant melanoma—a disease that is commonly treated with inhibitors of the mitogen-activated protein kinase (MAPK) pathway—Wellbrock and colleagues examined the expression of MITF, which is regulated by MAPK signaling and has been implicated in resistance to MAPK inhibitors. In cell lines, xenograft tumors, and human patient-derived tumors, MITF levels increased following initial treatment with MAPK inhibitors. This increase in MITF expression, which could be reversed with drug removal, was driven by the transcription factor PAX3 and was sufficient to drive a reversible MAPK inhibitor–resistant or “tolerant” state. By screening a library of 640 FDA-approved drugs, the authors identified the HIV-1 protease inhibitor nelfinavir as a potent suppressor of PAX3/MITF expression that could reverse MITF-driven drug tolerance. The authors found that nelfinavir enhanced SMAD2 activation, the subsequent formation of a SMAD2/SMAD4/SKI transcriptional repressor complex, and the complex’s repression of PAX3 expression. Nelfinavir also sensitized BRAF mutant melanoma tumors to MAPK inhibitors in vivo, a result that was further extended to both NRAS mutant melanomas as well as BRAF mutant tumors with NRAS-driven therapeutic resistance.

This work adds to a growing body of literature suggesting that the evolution of tumor cells to a fully drug-resistant state may often proceed through a reversible drug-tolerant phase, and that targeting this phase at the point of therapy initiation may improve both the depth and duration of therapeutic response. In melanoma, it is clear that PAX3/MITF critically regulates this reversible drug tolerance, and that this axis can be pharmacologically manipulated using a repurposed drug already known to be safe in humans.

M. P. Smith et al., Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 29, 270–284 (2016). [Abstract]

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