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MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB

Overview of attention for article published in Clinical Cancer Research, December 2016
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Title
MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB
Published in
Clinical Cancer Research, December 2016
DOI 10.1158/1078-0432.ccr-16-1192
Pubmed ID
Authors

April A.N. Rose, Matthew G. Annis, Dennie T. Frederick, Marco Biondini, Zhifeng Dong, Lawrence Kwong, Lynda Chin, Tibor Keler, Thomas Hawthorne, Ian R. Watson, Keith T. Flaherty, Peter M. Siegel

Abstract

To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB. The TCGA melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot and FACs analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from melanoma patients taken before, during and after disease progression on MAPK inhibitor treatment. Sub-cutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth. A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pre-treatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug-conjugate targeting GPNMB, is effective in causing melanoma regression in pre-clinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone. The combination of MAPK pathway inhibitors with an antibody-drug-conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 50 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 50 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 10 20%
Student > Ph. D. Student 7 14%
Other 4 8%
Student > Bachelor 3 6%
Professor 3 6%
Other 12 24%
Unknown 11 22%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 11 22%
Agricultural and Biological Sciences 8 16%
Medicine and Dentistry 7 14%
Pharmacology, Toxicology and Pharmaceutical Science 3 6%
Engineering 2 4%
Other 7 14%
Unknown 12 24%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 2. 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 19 December 2016.
All research outputs
#13,986,547
of 22,882,389 outputs
Outputs from Clinical Cancer Research
#9,696
of 12,605 outputs
Outputs of similar age
#222,349
of 420,820 outputs
Outputs of similar age from Clinical Cancer Research
#125
of 206 outputs
Altmetric has tracked 22,882,389 research outputs across all sources so far. This one is in the 37th percentile – i.e., 37% of other outputs scored the same or lower than it.
So far Altmetric has tracked 12,605 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.8. This one is in the 21st percentile – i.e., 21% of its peers scored the same or lower than it.
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 420,820 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 45th percentile – i.e., 45% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 206 others from the same source and published within six weeks on either side of this one. This one is in the 35th percentile – i.e., 35% of its contemporaries scored the same or lower than it.