Abstract
BackgroundDasatinib (Sprycel) was developed as a tyrosine kinase inhibitor targeting Bcr-Abl and the family of Src kinases. Dasatinib is commonly used for the treatment of acute lymphoblastic and chronic myelogenous leukemia. Previous clinical studies in melanoma returned inconclusive results and suggested that patients respond highly heterogeneously to dasatinib as single agent or in combination with standard-of-care chemotherapeutic dacarbazine. Reliable biomarkers to predict dasatinib responsiveness in melanoma have not yet been developed.ResultsHere, we collected comprehensive in vitro data from experimentally well-controlled conditions to study the effect of dasatinib, alone and in combination with dacarbazine, on cell proliferation and cell survival. Sixteen treatment conditions, covering therapeutically relevant concentrations ranges of both drugs, were tested in 12 melanoma cell lines with diverse mutational backgrounds. Melanoma cell lines responded heterogeneously and, importantly, dasatinib and dacarbazine did not synergize in suppressing proliferation or inducing cell death. Since dasatinib is a promiscuous kinase inhibitor, possibly affecting multiple disease-relevant pathways, we also determined if basal phospho-protein amounts and treatment-induced changes in phospho-protein levels are indicative of dasatinib responsiveness. We found that treatment-induced de-phosphorylation of p53 correlates with dasatinib responsiveness in malignant melanoma.ConclusionsLoss of p53 phosphorylation might be an interesting candidate for a kinetic marker of dasatinib responsiveness in melanoma, pending more comprehensive validation in future studies.
Highlights
Dasatinib (Sprycel) was developed as a tyrosine kinase inhibitor targeting Bcr-Abl and the family of Src kinases
The reduction of p53 phosphorylation was detected when examining S15 phosphorylation in whole cell extracts of untreated and dasatinib-treated SK-MEL-2 responder cells but not, as a Discussion Here, we studied the responsiveness of melanoma cells to dasatinib, alone or in combination with standardof-care chemotherapeutic dacarbazine, by systematically analyzing growth inhibition and cell death at therapeutically meaningful concentrations ranges of both drugs
We found that the amounts of p53 (S46) drop upon dasatinib treatment in responsive melanoma cell lines
Summary
Dasatinib (Sprycel) was developed as a tyrosine kinase inhibitor targeting Bcr-Abl and the family of Src kinases. Previous clinical studies in melanoma returned inconclusive results and suggested that patients respond highly heterogeneously to dasatinib as single agent or in combination with standard-of-care chemotherapeutic dacarbazine. Dasatinib (N-(2-chloro-6-methyl-phenyl)-2-((6-(4-(2hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-yl) amino)-1,3-thiazole-5-carboxamide) is an orally active tyrosine kinase inhibitor developed to target Bcr-Abl and the family of Src kinases [1]. The therapeutic efficacy of dasatinib was tested as a single treatment as well as in combination with the standard-of-care chemotherapeutic dacarbazine (DTIC) in phase I/II trials. Since the majority of melanoma patients in poorly funded healthcare environments to this day still do not have routine access to costly BRAFV600/MEK inhibitor or immunotherapeutics based treatments, these patients still rely on chemotherapy. We studied if pre-treatment phospho-protein amounts as well as their treatment-induced changes could serve as indicators for treatment responsiveness
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