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Título

Phospho-kinase profile of colorectal tumors guides in the selection of multi-kinase inhibitors

AutorSerrano-Heras, Gemma; Cuenca-López, María D.; Montero, Juan Carlos; Morales, Jorge C.; Pandiella, Atanasio; Ocaña, Alberto
Palabras claveEC-70124
Kinase inhibitors
Colon cancer
Fecha de publicación2015
EditorImpact Journals
CitaciónOncotarget 6(31): 31272-31283 (2015)
ResumenProtein kinases play a central role in the oncogenesis of colorectal tumors and are attractive druggable targets. Detection of activated kinases within a tumor could open avenues for drug selection and optimization of new kinase inhibitors. By using a phosphokinase arrays with human colorectal tumors we identified activated kinases, including the Epidermal Growth Factor Receptor (EGFR), components of the PI3K/mTOR pathway (AKT and S6), and STAT, among others. A pharmacological screening with kinase inhibitors against these proteins helped us to identify a new kinase inhibitor, termed EC-70124 that showed the highest anti-proliferative activity in cell lines. EC-70124 also inhibited cell migration and biochemical experiments demonstrated its effect targeting the PI3K/mTOR pathway. This drug also arrested cells at G2/M and induced apoptosis. Experiments in combination with standard chemotherapy used in the clinical setting indicated a synergistic effect. EC-70124 also reduced tumor growth in vivo and inhibited pS6 in the implanted tumors. In conclusion, by studying the kinase profile of colorectal tumors, we identified relevant activated pathways, and a new multi-kinase compound with significant antitumor properties.
DescripciónThis is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.
Versión del editorhttp://dx.doi.org/10.18632/oncotarget.5211
URIhttp://hdl.handle.net/10261/135731
DOI10.18632/oncotarget.5211
Identificadoresdoi: 10.18632/oncotarget.5211
e-issn: 1949-2553
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