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Vemurafenib resistance reprograms melanoma cells towards glutamine dependence

Overview of attention for article published in Journal of Translational Medicine, July 2015
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  • Above-average Attention Score compared to outputs of the same age (60th percentile)
  • Above-average Attention Score compared to outputs of the same age and source (61st percentile)

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4 tweeters

Citations

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43 Dimensions

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66 Mendeley
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Title
Vemurafenib resistance reprograms melanoma cells towards glutamine dependence
Published in
Journal of Translational Medicine, July 2015
DOI 10.1186/s12967-015-0581-2
Pubmed ID
Authors

Jenny E Hernandez-Davies, Thai Q Tran, Michael A Reid, Kimberly R Rosales, Xazmin H Lowman, Min Pan, Gatien Moriceau, Ying Yang, Jun Wu, Roger S Lo, Mei Kong

Abstract

(V600) BRAF mutations drive approximately 50% of metastatic melanoma which can be therapeutically targeted by BRAF inhibitors (BRAFi) and, based on resistance mechanisms, the combination of BRAF and MEK inhibitors (BRAFi + MEKi). Although the combination therapy has been shown to provide superior clinical benefits, acquired resistance is still prevalent and limits the overall survival benefits. Recent work has shown that oncogenic changes can lead to alterations in tumor cell metabolism rendering cells addicted to nutrients, such as the amino acid glutamine. Here, we evaluated whether melanoma cells with acquired resistance display glutamine dependence and whether glutamine metabolism can be a potential molecular target to treat resistant cells. Isogenic BRAFi sensitive parental (V600) BRAF mutant melanoma cell lines and resistant (derived by chronic treatment with vemurafenib) sub-lines were used to assess differences in the glutamine uptake and sensitivity to glutamine deprivation. To evaluate a broader range of resistance mechanisms, isogenic pairs where the sub-lines were resistant to BRAFi + MEKi were also studied. Since resistant cells demonstrated increased sensitivity to glutamine deficiency, we used glutaminase inhibitors BPTES [bis-2-(5 phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide] and L-L-DON (6-Diazo-5-oxo-L-norleucine) to treat MAPK pathway inhibitor (MAPKi) resistant cell populations both in vitro and in vivo. We demonstrated that MAPKi-acquired resistant cells uptook greater amounts of glutamine and have increased sensitivity to glutamine deprivation than their MAPKi-sensitive counterparts. In addition, it was found that both BPTES and L-DON were more effective at decreasing cell survival of MAPKi-resistant sub-lines than parental cell populations in vitro. We also showed that mutant NRAS was critical for glutamine addiction in mutant NRAS driven resistance. When tested in vivo, we found that xenografts derived from resistant cells were more sensitive to BPTES or L-DON treatment than those derived from parental cells. Our study is a proof-of-concept for the potential of targeting glutamine metabolism as an alternative strategy to suppress acquired MAPKi-resistance in melanoma.

Twitter Demographics

The data shown below were collected from the profiles of 4 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 66 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Luxembourg 1 2%
Unknown 65 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 19 29%
Researcher 10 15%
Unspecified 8 12%
Student > Master 8 12%
Student > Bachelor 7 11%
Other 14 21%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 17 26%
Agricultural and Biological Sciences 17 26%
Unspecified 13 20%
Medicine and Dentistry 7 11%
Pharmacology, Toxicology and Pharmaceutical Science 4 6%
Other 8 12%

Attention Score in Context

This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 15 July 2015.
All research outputs
#6,023,872
of 11,428,083 outputs
Outputs from Journal of Translational Medicine
#763
of 2,210 outputs
Outputs of similar age
#89,293
of 235,772 outputs
Outputs of similar age from Journal of Translational Medicine
#34
of 101 outputs
Altmetric has tracked 11,428,083 research outputs across all sources so far. This one is in the 46th percentile – i.e., 46% of other outputs scored the same or lower than it.
So far Altmetric has tracked 2,210 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 7.2. This one has gotten more attention than average, scoring higher than 62% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 235,772 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 60% of its contemporaries.
We're also able to compare this research output to 101 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 61% of its contemporaries.