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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

Cartoon representing selected pathways detected by (phospho)proteomic analysisUp-regulated or down-regulated proteins/phosphosites are indicated by a green or red arrow, respectively. Proteins regulated at 1 day/control only, 3 days/control only and entries regulated in both time points are labeled in orange, blue and pink, respectively. Proteins that have not been identified or whose expression levels are not changing are labeled in black. ROCK1 has been highlighted by an orange star as potential co-target in combination with PLX4720 therapy according to our integrated proteomic and genomic approach.
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fig07: Cartoon representing selected pathways detected by (phospho)proteomic analysisUp-regulated or down-regulated proteins/phosphosites are indicated by a green or red arrow, respectively. Proteins regulated at 1 day/control only, 3 days/control only and entries regulated in both time points are labeled in orange, blue and pink, respectively. Proteins that have not been identified or whose expression levels are not changing are labeled in black. ROCK1 has been highlighted by an orange star as potential co-target in combination with PLX4720 therapy according to our integrated proteomic and genomic approach.

Mentions: Here, we applied an unbiased multi-angle approach to discover new potential targets that render melanoma more sensitive to clinically relevant inhibitors of the BRAF pathway, particularly those targeting BRAF and ERK. As a model system, we used a panel of BRAF mutant human melanoma cell lines sensitive to PLX4720 treatment. Interestingly, although we used a sensitive cell line in our proteomic platform, we detected elevated expression of several proteins that have previously been reported to be involved in resistance. They include NRAS, Erbb3 and Src, and the transcription factor FOXD3 (Fig7). These observations raise the interesting possibility that melanoma cells activate multiple different pathways involved in resistance already very early on, as soon as they are exposed to targeted inhibition of driver oncoproteins. Our data provide a resource for future studies aiming to resolve the mechanism by which certain responses are selected in pathways leading to drug resistance and survival of the melanoma cells. Indeed, as we show here, the impairment of one of these drug-regulated pathways can be effective in improving current targeted melanoma therapies.


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)

Cartoon representing selected pathways detected by (phospho)proteomic analysisUp-regulated or down-regulated proteins/phosphosites are indicated by a green or red arrow, respectively. Proteins regulated at 1 day/control only, 3 days/control only and entries regulated in both time points are labeled in orange, blue and pink, respectively. Proteins that have not been identified or whose expression levels are not changing are labeled in black. ROCK1 has been highlighted by an orange star as potential co-target in combination with PLX4720 therapy according to our integrated proteomic and genomic approach.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig07: Cartoon representing selected pathways detected by (phospho)proteomic analysisUp-regulated or down-regulated proteins/phosphosites are indicated by a green or red arrow, respectively. Proteins regulated at 1 day/control only, 3 days/control only and entries regulated in both time points are labeled in orange, blue and pink, respectively. Proteins that have not been identified or whose expression levels are not changing are labeled in black. ROCK1 has been highlighted by an orange star as potential co-target in combination with PLX4720 therapy according to our integrated proteomic and genomic approach.
Mentions: Here, we applied an unbiased multi-angle approach to discover new potential targets that render melanoma more sensitive to clinically relevant inhibitors of the BRAF pathway, particularly those targeting BRAF and ERK. As a model system, we used a panel of BRAF mutant human melanoma cell lines sensitive to PLX4720 treatment. Interestingly, although we used a sensitive cell line in our proteomic platform, we detected elevated expression of several proteins that have previously been reported to be involved in resistance. They include NRAS, Erbb3 and Src, and the transcription factor FOXD3 (Fig7). These observations raise the interesting possibility that melanoma cells activate multiple different pathways involved in resistance already very early on, as soon as they are exposed to targeted inhibition of driver oncoproteins. Our data provide a resource for future studies aiming to resolve the mechanism by which certain responses are selected in pathways leading to drug resistance and survival of the melanoma cells. Indeed, as we show here, the impairment of one of these drug-regulated pathways can be effective in improving current targeted melanoma therapies.

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