Serrano-Heras Gemma, Cuenca-López María Dolores, Montero Juan Carlos, Corrales-Sanchez Verónica, Morales Jorge Carlos, Núñez Luz-Elena, Morís Francisco, Pandiella Atanasio, Ocaña Alberto
Translational Research Unit, Albacete University Hospital, Albacete, Spain.
Cancer Research Center, CSIC-University of Salamanca, Salamanca, Spain.
Oncotarget. 2015 Oct 13;6(31):31272-83. doi: 10.18632/oncotarget.5211.
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.
蛋白激酶在结直肠癌的肿瘤发生过程中起着核心作用，是颇具吸引力的可成药靶点。检测肿瘤内活化的激酶可为药物选择和新型激酶抑制剂的优化开辟道路。通过使用针对人类结直肠癌的磷酸激酶阵列，我们鉴定出了活化的激酶，包括表皮生长因子受体（EGFR）、PI3K/mTOR通路的组分（AKT和S6）以及STAT等。用针对这些蛋白的激酶抑制剂进行的药理筛选帮助我们鉴定出一种名为EC-70124的新型激酶抑制剂，它在细胞系中表现出最高的抗增殖活性。EC-70124还抑制细胞迁移，生化实验证明了其靶向PI3K/mTOR通路的作用。这种药物还使细胞停滞在G2/M期并诱导细胞凋亡。与临床使用的标准化疗联合进行的实验表明存在协同效应。EC-70124还能在体内降低肿瘤生长，并抑制植入肿瘤中的pS6。总之，通过研究结直肠癌的激酶谱，我们鉴定出了相关的活化通路以及一种具有显著抗肿瘤特性的新型多激酶化合物。
