不同原发部位骨肉瘤药物靶点的蛋白质基因组学研究

Rei Noguchi, Yuki Yoshimatsu, T. Ono, Akane Sei, T. Kondo
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引用次数: 1

摘要

激酶活性的调节在癌变和癌症进展中起着至关重要的作用。激酶活性域的突变作为治疗靶点被广泛研究。我们通过多组学方法研究了抗增殖抗癌药物和药物靶点:(1)综合激酶活性测定,(2)高通量药物筛选,(3)基因组测序。使用分别来源于骨和软组织的两种骨肉瘤细胞系nc - os1 - c1和nc - esos1 - c1。NCC oncoppanel基于下一代测序技术和SNP阵列检测遗传改变。通过PamStation 12(一种体外激酶测定法)监测100种激酶。研究了214种fda批准的抗癌药物的抗增殖作用。在NCC-ESOS1-C1中发现了PIK3CA突变和CDKN2A缺失,而在NCC-OS1-C1中未发现可药物的遗传改变。PI3K-AKT通路或CDKN2A抑制剂对这些细胞系没有显着影响。综合动力学分析显示这些骨肉瘤细胞间无显著差异(R2=0.99)。这两个细胞具有相似的FES、FER、PDGFR-β、VEGFR2和Wee1激酶活性谱。抗癌药物对nc - os1 - c1和nc - esos1细胞的抗增殖作用有显著差异。对罗米地辛和trabectedin均有显著反应。艾力布林对NCCOS1-C1有效;异环磷酰胺和达卡巴嗪仅对nc - esos1 - c1有效。因此,研究激酶活性和基因改变将有助于预测激酶抑制剂的作用。不同状态的激酶突变、活性和对抑制剂的反应应该综合考虑。多组学实验和数据整合对于了解癌症进展和开发新的治疗方法至关重要。
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Proteogenomic approach to drug targets in osteosarcomas with different original sites
Regulation of kinase activity plays a crucial role in carcinogenesis and cancer progression. Mutations in the activity domain of kinases are extensively investigated as therapeutic targets. We examined anti-proliferative anti-cancer drugs and drug targets via the multi-omics approach: (i) comprehensive kinase activity assay, (ii) high-throughput drug screening, and (iii) genomic sequencing. Two osteosarcomas cell lines, NCC-OS1-C1 and NCC-ESOS1-C1 derived from bone and soft tissue respectively, were used. Genetic alterations were examined by NCC Oncopanel based on the next-generation sequencing technology and SNP array. One hundred kinases were monitored by the PamStation 12, an in vitro kinase assay. The anti-proliferative effects of 214 FDA-approved anti-cancer drugs were examined. Mutation of PIK3CA and deletion of CDKN2A were identified in NCC-ESOS1-C1 and druggable genetic alterations were not identified in the NCC-OS1-C1. PI3K-AKT pathway or CDKN2A inhibitors did not show significant effects on these cell lines. Comprehensive kinomic assay revealed no remarkable differences on these osteosarcoma cells (R2=0.99). The two cells shared similar kinase activity profiles for FES, FER, PDGFR-β, VEGFR2, and Wee1. Anti-proliferative effects of anti-cancer drugs on NCC-OS1-C1 and NCC-ESOS1 cells showed remarkable differences. Significant responses to romidepsin and trabectedin were observed for both. Eribulin was effective on NCCOS1-C1; ifosfamide and dacarbazine were effective on NCC-ESOS1-C1 only. Hence, investigating kinase activities and genetic alterations will lead to predict the effects of kinase inhibitors. The different status of kinase mutations, activities, and response to inhibitors should be integrated. Multi-omics experiments and data integration are crucial in understanding cancer progression and developing novel therapies.
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Electrophoretic extraction of protein complexes after separation and detection by a combined method of non-denaturing two-dimensional electrophoresis and reversible staining Use of Escherichia coli expression system for analyzing kinase motifs Proteomic analysis of spheroids of rhabdomyosarcoma cells cultured with decellularized muscle extracts Drug screening and kinase activity profiling of a novel patient-derived cell line of clear cell ovarian carcinoma Proteogenomic approach to drug targets in osteosarcomas with different original sites
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