Limits...
ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma.

Smit MA, Maddalo G, Greig K, Raaijmakers LM, Possik PA, van Breukelen B, Cappadona S, Heck AJ, Altelaar AF, Peeper DS - Mol. Syst. Biol. (2014)

Bottom Line: However, most patients eventually relapse due to drug resistance.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

No MeSH data available.


Related in: MedlinePlus

Targeted ROCK inhibition increases the toxicity of inhibitors of the MAPK pathwayThree independent melanoma cell lines (04.01, 93.03 and 04.07) were treated with dilution series of PLX4720 either alone or in combination with the ROCK inhibitor GSK269962A. After 3 days, cell viability was determined by a cell titer blue assay and represented in the y-axis.Cells were treated same as in (A), but with a dilution series of the ERK inhibitor SCH772984.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4300494&req=5

fig06: Targeted ROCK inhibition increases the toxicity of inhibitors of the MAPK pathwayThree independent melanoma cell lines (04.01, 93.03 and 04.07) were treated with dilution series of PLX4720 either alone or in combination with the ROCK inhibitor GSK269962A. After 3 days, cell viability was determined by a cell titer blue assay and represented in the y-axis.Cells were treated same as in (A), but with a dilution series of the ERK inhibitor SCH772984.

Mentions: To begin to translate these findings to a more clinically relevant setting, we turned to pharmacologic inhibition of ROCK. The ROCK inhibitor fasudil is being used for treatment of cerebral vasospasms (Olson, 2008). We examined whether inhibition of ROCK1 with a pharmacological inhibitor could have an additive effect on BRAF or ERK inhibition. For this purpose, we used GSK269962A, an inhibitor targeting ROCK1 and ROCK2, which has been shown to have vasodilatory effects in rats (Doe et al, 2007) and which is more specific than fasudil. We treated six different low-passage melanoma cell lines with a dilution series of PLX4720 or SCH772984 with or without a fixed concentration of the ROCK inhibitor. Indeed, addition of the ROCK inhibitor profoundly enhanced the effect of either PLX4720 or SCH772984 to induce melanoma cell death (Fig6A and B, Supplementary Fig S4). Furthermore, in the 93.03 and A375 melanoma cell lines, addition of ROCK inhibitor eliminated the population of residual cells that survived at the highest PLX4720 or SCH772984 concentration. This suggests that combined treatment with a ROCK inhibitor and a BRAF inhibitor may be beneficial for patients with BRAF mutant melanoma.


ROCK1 is a potential combinatorial drug target for BRAF mutant melanoma.

Smit MA, Maddalo G, Greig K, Raaijmakers LM, Possik PA, van Breukelen B, Cappadona S, Heck AJ, Altelaar AF, Peeper DS - Mol. Syst. Biol. (2014)

Targeted ROCK inhibition increases the toxicity of inhibitors of the MAPK pathwayThree independent melanoma cell lines (04.01, 93.03 and 04.07) were treated with dilution series of PLX4720 either alone or in combination with the ROCK inhibitor GSK269962A. After 3 days, cell viability was determined by a cell titer blue assay and represented in the y-axis.Cells were treated same as in (A), but with a dilution series of the ERK inhibitor SCH772984.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4300494&req=5

fig06: Targeted ROCK inhibition increases the toxicity of inhibitors of the MAPK pathwayThree independent melanoma cell lines (04.01, 93.03 and 04.07) were treated with dilution series of PLX4720 either alone or in combination with the ROCK inhibitor GSK269962A. After 3 days, cell viability was determined by a cell titer blue assay and represented in the y-axis.Cells were treated same as in (A), but with a dilution series of the ERK inhibitor SCH772984.
Mentions: To begin to translate these findings to a more clinically relevant setting, we turned to pharmacologic inhibition of ROCK. The ROCK inhibitor fasudil is being used for treatment of cerebral vasospasms (Olson, 2008). We examined whether inhibition of ROCK1 with a pharmacological inhibitor could have an additive effect on BRAF or ERK inhibition. For this purpose, we used GSK269962A, an inhibitor targeting ROCK1 and ROCK2, which has been shown to have vasodilatory effects in rats (Doe et al, 2007) and which is more specific than fasudil. We treated six different low-passage melanoma cell lines with a dilution series of PLX4720 or SCH772984 with or without a fixed concentration of the ROCK inhibitor. Indeed, addition of the ROCK inhibitor profoundly enhanced the effect of either PLX4720 or SCH772984 to induce melanoma cell death (Fig6A and B, Supplementary Fig S4). Furthermore, in the 93.03 and A375 melanoma cell lines, addition of ROCK inhibitor eliminated the population of residual cells that survived at the highest PLX4720 or SCH772984 concentration. This suggests that combined treatment with a ROCK inhibitor and a BRAF inhibitor may be beneficial for patients with BRAF mutant melanoma.

Bottom Line: However, most patients eventually relapse due to drug resistance.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

No MeSH data available.


Related in: MedlinePlus