title: Evaluating the promiscuous nature of tyrosine kinase inhibitors assessed in A431 epidermoid carcinoma cells by both chemical- and phosphoproteomics.
abstract: Deregulation of protein tyrosine kinase signaling has been linked to many diseases, most notably cancer. As a consequence, small molecule inhibitors of protein tyrosine kinases may provide powerful strategies for treatment. Following the successful introduction of imatinib in the treatment of chronic myelogenous leukemia, such drugs are also now evaluated for other types of cancer. However, many developed kinase inhibitors are not very target-specific and therefore may induce side effects. The importance of such side effects is certainly cell-proteome dependent. Understanding the all-inclusive action of a tyrosine kinase inhibitor on each individual cell-type entails the identification of potential targets, combined with monitoring the downstream effects revealing the signaling networks involved. Here, we explored a multilevel quantitative mass spectrometry-based proteomic strategy to identify the direct targets and downstream signaling effect of four tyrosine kinase inhibitors (imatinib, dasatinib, bosutinib, and nilotinib) in epidermoid carcinoma cells, as a model system for skin-cancer. More than 25 tyrosine kinases showed affinity to the drugs, with imatinib and nilotinib displaying a high specificity, especially when compared to dasatinib and bosutinib. Consequently, the latter two drugs showed a larger effect on downstream phosphotyrosine signaling. Many of the proteins affected are key regulators in cell adhesion and invasion. Our data represents a multiplexed view on the promiscuous action of certain tyrosine kinase inhibitors that needs to be taking into consideration prior to the application of these drugs in the treatment of different forms of cancer.
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University , Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Piero
authors.initials: P
authors.lastname: Giansanti
authors.forename: Christian
authors.initials: C
authors.lastname: Preisinger
authors.forename: Kilian V M
authors.initials: KV
authors.lastname: Huber
authors.forename: Manuela
authors.initials: M
authors.lastname: Gridling
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Albert J R
authors.initials: AJ
authors.lastname: Heck
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology*; D045744:Cell Line, Tumor; D006801:Humans; D013058:Mass Spectrometry; D010766:Phosphorylation; D060066:Protein Interaction Maps / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology*
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases