Treatment of BRAF mutant melanomas with specific BRAF inhibitors\nleads to tumor remission. However, most patients eventually\nrelapse due to drug resistance. Therefore, we designed an integrated\nstrategy using (phospho)proteomic and functional genomic\nplatforms to identify drug targets whose inhibition sensitizes\nmelanoma cells to BRAF inhibition. We found many proteins to be\ninduced upon PLX4720 (BRAF inhibitor) treatment that are known\nto be involved in BRAF inhibitor resistance, including FOXD3 and\nErbB3. Several proteins were down-regulated, including Rnd3, a\nnegative regulator of ROCK1 kinase. For our genomic approach, we\nperformed two parallel shRNA screens using a kinome library to\nidentify genes whose inhibition sensitizes to BRAF or ERK inhibitor\ntreatment. By integrating our functional genomic and (phospho)\nproteomic data, we identified ROCK1 as a potential drug target for\nBRAF mutant melanoma. ROCK1 silencing increased melanoma cell\nelimination when combined with BRAF or ERK inhibitor treatment.\nTranslating this to a preclinical setting, a ROCK inhibitor showed\naugmented melanoma cell death upon BRAF or ERK inhibition\nin vitro. These data merit exploration of ROCK1 as a target in\ncombination with current BRAF mutant melanoma therapies.
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