Evaluating the Promiscuous Nature of Tyrosine Kinase Inhibitors Assessed in A431 Epidermoid Carcinoma Cells by Both Chemical- and Phosphoproteomics

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.