Antitumoral activity of EC70124, a novel multitarget kinase inhibitor, in triple-negative breast cancer.

Cuenca-López, María D.; Montero, Juan Carlos; Serrano‐Heras, Gemma; Corrales-Sánchez, Verónica; Morales, Jorge C.; Morís, Francisco; Pandiella, Atanasio; Fernandez, A. Ocana

doi:10.1200/jco.2014.32.15_suppl.1116

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“…As success in cancer therapy is based on drug combinations, we investigated the effect of EC-70124 in association with chemotherapies used in the clinical setting for the treatment of metastatic colorectal cancer including irinotecan, 5-fluorouracil and oxaliplatin. To identify synergistic interactions we used the Chou-Talalay algorithm [ 12 ] for combination index analysis in SW620 and HT29, at different concentrations (Figure 5A ). Combinations with irinotecan, oxaliplatin and 5-fluorouracil were synergistic in the two cell lines, at almost all evaluated doses (Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether EC-70124 combined to other chemotherapy drugs (Irinotecan, Oxaliplatin or 5-Fluorouracil) was synergistic, additive, or antagonist, we used the CalcuSyn v2.0 software programme (Biosoft, Ferguson, MO). This program allows the calculation of the combination index based on the algorithm of Chou and Talalay [ 12 ]. Combination index values greater than 1 indicate antagonism, less than 1 indicate synergism and values equal to 1 indicate an additive effect.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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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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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%