Dasatinib is a multi-target
kinase inhibitor, whose targets include BCR-ABL,
SRC family kinases, and various
cancer kinases. The elevated SRC activity in
gastric cancer (GC) has prompted the need for the therapeutic application of
dasatinib in GC. We observed that the efficacy of
dasatinib varied with the GC cell lines. The differential effect of
dasatinib was not correlated with the basal SRC activity of each cell line. Moreover, the GC cell lines showing the strong antitumor effects of
dasatinib were refractory to other SRC inhibitors, i.e.,
bosutinib and
saracatinib, suggesting that unexpected
dasatinib's targets could exist. To profile the targets of
dasatinib in GC, we performed activity-based
protein profiling (ABPP) via mass spectrometry using a
desthiobiotin-
ATP probe. We identified 29 and 18
kinases as potential targets in
dasatinib-sensitive (SNU-216, MKN-1) and -resistant (SNU-484, SNU-601) cell lines, respectively. The
protein-
protein interaction mapping of the differential drug targets in
dasatinib-sensitive and -resistant GC using the STRING database suggested that
dasatinib could target cellular energy homeostasis in the drug-sensitive GC. RNAi screening for identified targets indicated p90RSK could be a novel
dasatinib target, which is important for maintaining the viability and motility of GC cells. Further functional validation of
dasatinib off-target actions will provide more effective therapeutic options for GC.