Inhibiting drivers of non-mutational drug-tolerance is a salvage strategy for targeted melanoma therapy

SMITH MP, BRUNTON H, ROWLING E, FERGUSON J, AROZARENA I, LEE JL, MISKOLCZI Z, GIROTTI MR*, MARAIS R, LEVESQUE MP, DUMMER R, FREDERICK DT, FLAHERTY KT, COOPER ZA, WARGO JA AND WELLBROCK C.

CANCER CELL

CELL PRESS

Lugar: United States; Año: 2016 p. 270 - 284

1535-6108

"Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-""targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant mela- noma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant mela- noma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/ PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could""improve current approaches of targeted melanoma therapy."