title: Phospho-kinase profile of colorectal tumors guides in the selection of multi-kinase inhibitors.
abstract: 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.
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Serrano-Heras
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Cuenca-López
authors.affiliation: Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Corrales-Sanchez
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Jorge Carlos
authors.initials: JC
authors.lastname: Morales
authors.affiliation: EntreChem S.L., Oviedo, Spain.
authors.forename: Luz-Elena
authors.initials: LE
authors.lastname: Núñez
authors.affiliation: EntreChem S.L., Oviedo, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Morís
authors.affiliation: Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ocaña
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D040081:Protein Array Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases
keywords: EC-70124; colon cancer; kinase inhibitors