Mass spectrometry-based technologies are increasingly utilized in drug discovery. Phosphoproteomics in particular
has allowed for the efficient surveying of phosphotyrosine signaling pathways involved in various diseases states,
most prominently in cancer. We describe a phosphotyrosine-based proteomics screening approach to identify signaling
pathways and tyrosine kinase inhibitor targets in highly tumorigenic human lymphoma-like primary cells. We identified
several receptor tyrosine kinase pathways and validated SRC family kinases (SFKs) as potential drug targets for targeted
selection of small molecule inhibitors. BMS-354825 (dasatinib) and SKI-606 (bosutinib), second and third generation
clinical SFK/ABL inhibitors, were found to be potent cytotoxic agents against tumorigenic cells with low toxicity to normal
pediatric stem cells. Both SFK inhibitors reduced ERK1/2 and AKT phosphorylation and induced apoptosis. This
study supports the adaptation of high-end mass spectrometry techniques for the efficient identification of candidate tyrosine
kinases as novel therapeutic targets in primary cancer cell lines.
Keywords: Bosutinib, BMS-354825, dasatinib, kinase inhibitors, phosphoproteomics, SKI-606, Src family kinases.
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