Phospho-kinase profile of colorectal tumors guides in the selection of multi-kinase inhibitors
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Gemma Serrano-Heras1,*, María Dolores Cuenca-López1,*, Juan Carlos Montero2, Verónica Corrales-Sanchez1, Jorge Carlos Morales1, Luz-Elena Núñez3, Francisco Morís3, Atanasio Pandiella2, Alberto Ocaña1
1Translational Research Unit, Albacete University Hospital, Albacete, Spain
2Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain
3EntreChem S.L., Oviedo, Spain
*These authors have contributed equally to this work
Keywords: colon cancer, EC-70124, kinase inhibitors
Received: July 03, 2015 Accepted: September 10, 2015 Published: September 22, 2015
Protein 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.
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