Montenegro Raquel Carvalho, Howarth Alison, Ceroni Alessandro, Fedele Vita, Farran Batoul, Mesquita Felipe Pantoja, Frejno Martin, Berger Benedict-Tilman, Heinzlmeir Stephanie, Sailem Heba Z, Tesch Roberta, Ebner Daniel, Knapp Stefan, Burbano Rommel, Kuster Bernhard, Müller Susanne
Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, Brazil.
Novo Nordisk Research Centre Oxford (NNRCO), Discovery Technologies and Genomics, Oxford, UK.
Oncotarget. 2020 Feb 4;11(5):535-549. doi: 10.18632/oncotarget.27462.
Gastric cancer (GC) remains the third leading cause of cancer-related death despite several improvements in targeted therapy. There is therefore an urgent need to investigate new treatment strategies, including the identification of novel biomarkers for patient stratification. In this study, we evaluated the effect of FDA-approved kinase inhibitors on GC. Through a combination of cell growth, migration and invasion assays, we identified dasatinib as an efficient inhibitor of GC proliferation. Mass-spectrometry-based selectivity profiling and subsequent knockdown experiments identified members of the SRC family of kinases including , , and , as well as other kinases such as , , , , , and as dasatinib targets. The expression levels of the identified kinases were investigated on RNA and protein level in 200 classified tumor samples from patients, who had undergone gastrectomy, but had received no treatment. Levels of FRK, DDR1 and SRC expression on both mRNA and protein level were significantly higher in metastatic patient samples regardless of the tumor stage, while expression levels of SIK2 correlated with tumor size. Collectively, our data suggest dasatinib for treatment of GC based on its unique property, inhibiting a small number of key kinases (SRC, FRK, DDR1 and SIK2), highly expressed in GC patients.
尽管靶向治疗有了一些进展，但胃癌（GC）仍是癌症相关死亡的第三大主要原因。因此，迫切需要研究新的治疗策略，包括确定用于患者分层的新型生物标志物。在本研究中，我们评估了美国食品药品监督管理局（FDA）批准的激酶抑制剂对GC的作用。通过细胞生长、迁移和侵袭试验相结合，我们确定达沙替尼是GC增殖的有效抑制剂。基于质谱的选择性分析和随后的敲低实验确定了SRC激酶家族的成员，包括 、 、 和 ，以及其他激酶，如 、 、 、 、 和 ，作为达沙替尼的靶点。在200例接受了胃切除术但未接受过治疗的患者的分类肿瘤样本中，对所确定激酶的RNA和蛋白质水平的表达进行了研究。无论肿瘤分期如何，转移性患者样本中FRK、DDR1和SRC在mRNA和蛋白质水平上的表达均显著更高，而SIK2的表达水平与肿瘤大小相关。总体而言，我们的数据表明，基于达沙替尼独特的特性，即抑制在GC患者中高表达的少数关键激酶（SRC、FRK、DDR1和SIK2），可用于治疗GC。
