ArticlePloS one2013
Differential inhibition of ex-vivo tumor kinase activity by vemurafenib in BRAF(V600E) and BRAF wild-type metastatic malignant melanoma.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 29 citations in OpenAlex.
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- Proteomic approach toward determining the molecular background of pazopanib resistance in synovial sarcoma.Oncotarget · 2017Article
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- KMT2A promotes melanoma cell growth by targeting hTERT signaling pathway.Cell death & disease · 2017Article
- Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy.Cancer research and treatment · 2017Article
- Integrating functional genomics to accelerate mechanistic personalized medicine.Cold Spring Harbor molecular case studies · 2017Review
- Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways.Frontiers in microbiology · 2017Article
- Evaluation of a tyrosine kinase peptide microarray for tyrosine kinase inhibitor therapy selection in cancer.Experimental & molecular medicine · 2016Article
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTreatment of metastatic malignant melanoma patients harboring BRAF(V600E) has improved drastically after the discovery of the BRAF inhibitor, vemurafenib. However, drug resistance is a recurring problem, and prognoses are still very bad for patients harboring BRAF wild-type. Better markers for targeted therapy are therefore urgently needed. METHODOLOGY: In this study, we assessed the individual kinase activity profiles in 26 tumor samples obtained from patients with metastatic malignant melanoma using peptide arrays with 144 kinase substrates. In addition, we studied the overall ex-vivo inhibitory effects of vemurafenib and sunitinib on kinase activity status.
resultsOverall kinase activity was significantly higher in lysates from melanoma tumors compared to normal skin tissue. Furthermore, ex-vivo incubation with both vemurafenib and sunitinib caused significant decrease in phosphorylation of kinase substrates, i.e kinase activity. While basal phosphorylation profiles were similar in BRAF wild-type and BRAF(V600E) tumors, analysis with ex-vivo vemurafenib treatment identified a subset of 40 kinase substrates showing stronger inhibition in BRAF(V600E) tumor lysates, distinguishing the BRAF wild-type and BRAF(V600E) tumors. Interestingly, a few BRAF wild-type tumors showed inhibition profiles similar to BRAF(V600E) tumors. The kinase inhibitory effect of vemurafenib was subsequently analyzed in cell lines harboring different BRAF mutational status with various vemurafenib sensitivity in-vitro.
conclusionsOur findings suggest that multiplex kinase substrate array analysis give valuable information about overall tumor kinase activity. Furthermore, intra-assay exposure to kinase inhibiting drugs may provide a useful tool to study mechanisms of resistance, as well as to identify predictive markers.
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