MITF Drives a Reversible Drug-Tolerant State in Melanoma

BRAF-mutant melanomas are sensitive to inhibition of MAPK signaling with BRAF and MEK inhibitors; however, the acquisition of drug resistance mutations leads to irreversible MAPK activation and disease progression. The mutational heterogeneity presents a challenge for treatment, which might be circumvented by early targeted treatments before the acquisition of resistance mutations. The melanocyte transcription factor MITF has been shown to promote MAPK inhibitor resistance, prompting Smith, Brunton, and colleagues to investigate its role in early adaptive responses after MAPK inhibitor treatment. In 9 of 11 patients with melanoma, MITF was upregulated within 2 weeks of treatment with BRAF and/or MEK inhibitors, and in mouse melanoma models, BRAF inhibition also upregulated MITF and promoted BRAF inhibitor tolerance. MITF depletion resensitized the cells to BRAF inhibition, indicating not only that the drug-tolerant state requires MITF but also that it is reversible, and does not require mutations. PAX3 is a known regulator of MITF, and was shown to mediate the upregulation of MITF in response to MAPK inhibition. Thus, a screen of 640 FDA-approved drugs was performed to identify compounds that suppress PAX3 and MITF expression and therefore might prevent MAPK inhibitor tolerance. The drug with the strongest effect on PAX3 and MITF expression was the HIV1-protease inhibitor nelfinavir, which suppressed PAX3 expression through recruitment of the transcriptional repressors SKI, SMAD2, and SMAD4 to the PAX3 promoter. By abrogating MAPK inhibitor–induced upregulation of PAX3 and MITF, nelfinavir treatment sensitized BRAF-mutant melanoma cells to BRAF and MEK inhibition in vitro and in vivo. Nelfinavir also sensitized NRAS-mutant melanoma cells to MEK inhibition and suppressed the development of acquired resistance. Together, these results indicate that targeting MITF in the nonmutational drug tolerance phase may be effective in preventing or delaying MAPK inhibitor resistance, and suggest that further study of nelfinavir in BRAF- and NRAS-mutant melanoma may be warranted.

Smith MP, Brunton H, Rowling EJ, Ferguson J, Arozarena I, Miskolczi Z, et al. Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 2016;29:270–84.