Evaluation of FGFR3 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma.
Evaluation of FGFR3 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma.
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FGFR3 作为头颈鳞状细胞癌治疗靶点的评估。
DOI：
10.1007/s11523-016-0431-z
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发表时间：
2016
影响因子：
5.4
通讯作者：
Perner,Sven
中科院分区：
文献类型：
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作者：
vonMässenhausen,Anne;Deng,Mario;Billig,Hannah;Queisser,Angela;Vogel,Wenzel;Kristiansen,Glen;Schröck,Andreas;Bootz,Friedrich;Göke,Friederike;Franzen,Alina;Heasley,Lynn;Kirfel,Jutta;Brägelmann,Johannes;Perner,Sven
虽然头颈部鳞状细胞癌（HNSCC）是全球第六大常见肿瘤实体，但它仍然是一个临床挑战。大规模的探索性基因组项目已经确定了几个基因作为潜在的治疗靶点，包括成纤维细胞生长因子受体3 （FGFR3）。本研究的目的是研究野生型和突变FGFR3的生物学意义，以评估其作为HNSCC新治疗靶点的潜力。方法在大型HNSCC组织队列（n= 536）中分析FGFR3蛋白表达，并从癌症基因组图谱（TCGA;n= 520）中分析FGFR3 mRNA表达。此外，FGFR3野生型和突变型在体外过表达，并在BGJ398（一种特异性FGFR1-3抑制剂）治疗和不治疗的情况下评估增殖和迁移。结果：尽管两组患者的FGFR3表达在肿瘤进展过程中均下降，但在一小部分患者中观察到高FGFR3表达水平。在体外，FGFR3过表达导致增殖增加，而迁移没有改变。此外，fgfr3过表达的细胞对BGJ398更敏感。在血清减少的条件下，与野生型FGFR3相比，过表达FGFR3突变版本的细胞显示出更高的增殖，并且在很大程度上与野生型蛋白一样对BGJ398敏感。综上所述，本研究结果表明，尽管FGFR3在HNSSC进展过程中表达降低，但它在肿瘤细胞增殖中起重要作用，因此可能是患有这种令人沮丧的肿瘤实体的患者的潜在治疗靶点。
BackgroundAlthough head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3).AimsThe aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC.MethodsFGFR3 protein expression was analysed in a large HNSCC tissue cohort (n= 536) and FGFR3 mRNA expression from The Cancer Genome Atlas (TCGA;n= 520). Moreover, FGFR3 wild-type and mutant versions were overexpressed in vitro, and both proliferation and migration was assessed with and without BGJ398 (a specific FGFR1-3 inhibitor) treatment.ResultsAlthough FGFR3 expression for both cohorts decreased during tumour progression, high FGFR3 expression levels were observed in a small subset of patients. In vitro, FGFR3 overexpression led to increased proliferation, whereas migration was not altered. Moreover, FGFR3-overexpressing cells were more sensitive to BGJ398. Cells overexpressing FGFR3 mutant versions showed increased proliferation compared to wild-type FGFR3 under serum-reduced conditions and were largely as sensitive as the wild-type protein to BGJ398.ConclusionsTaken together, the results of this study demonstrate that although FGFR3 expression decreases during HNSSC progression, it plays an important role in tumour cell proliferation and thus may be a potential target for therapy in selected patients suffering from this dismal tumour entity.