Abstract
Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. However, most patients eventually relapse due to drug resistance. Therefore, we designed an integrated strategy using (phospho)proteomic and functional genomic platforms to identify drug targets whose inhibition sensitizes melanoma cells to BRAF inhibition. We found many proteins to be induced upon PLX4720 (BRAF inhibitor) treatment that are known to be involved in BRAF inhibitor resistance, including FOXD3 and ErbB3. Several proteins were down-regulated, including Rnd3, a negative regulator of ROCK1 kinase. For our genomic approach, we performed two parallel shRNA screens using a kinome library to identify genes whose inhibition sensitizes to BRAF or ERK inhibitor treatment. By integrating our functional genomic and (phospho)proteomic data, we identified ROCK1 as a potential drug target for BRAF mutant melanoma. ROCK1 silencing increased melanoma cell elimination when combined with BRAF or ERK inhibitor treatment. Translating this to a preclinical setting, a ROCK inhibitor showed augmented melanoma cell death upon BRAF or ERK inhibition in vitro. These data merit exploration of ROCK1 as a target in combination with current BRAF mutant melanoma therapies.
Highlights
Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission
We used a low-passage human melanoma cell line, 04.01, which is sensitive to treatment with PLX4720, a preclinical vemurafenib analog
We used a panel of BRAF mutant human melanoma cell lines sensitive to PLX4720 treatment
Summary
Treatment of BRAF mutant melanomas with specific BRAF inhibitors leads to tumor remission. Translating this to a preclinical setting, a ROCK inhibitor showed augmented melanoma cell death upon BRAF or ERK inhibition in vitro These data merit exploration of ROCK1 as a target in combination with current BRAF mutant melanoma therapies. Vemurafenib, a drug targeting BRAFV600E, has become the standard of care for patients diagnosed with mutant BRAF metastatic melanoma This compound or other drugs targeting other components of the MAPK pathway initially reduce tumor burden, eventually all melanomas become resistant and patients succumb to the disease (Flaherty et al, 2010; Chapman et al, 2011; Wagle et al, 2011). As vemurafenib is the best-characterized drug for melanoma treatment, we pursued a multi-angle approach, utilizing an integrated and unbiased proteomic and genetic screening platform to identify targets whose inhibition would increase the toxicity of vemurafenib toward melanoma cells
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