FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers.
FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers.
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DOI：
10.1158/1078-0432.ccr-14-3357
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发表时间：
2015-10-01
期刊：
影响因子：
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通讯作者：
Perner S
中科院分区：
文献类型：
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作者：
Göke F;Franzen A;Hinz TK;Marek LA;Yoon P;Sharma R;Bode M;von Maessenhausen A;Lankat-Buttgereit B;Göke A;Golletz C;Kirsten R;Boehm D;Vogel W;Kleczko EK;Eagles JR;Hirsch FR;Van Bremen T;Bootz F;Schroeck A;Kim J;Tan AC;Jimeno A;Heasley LE;Perner S
FGFR1拷贝数增加（CNG）发生在头颈部鳞状细胞癌（HNSCC）中，并用于fgfr特异性抑制剂临床试验中的患者选择。本研究探讨了FGFR1 mRNA和蛋白水平在HNSCC细胞系、原发肿瘤和患者来源的异种移植物（PDXs）中作为对FGFR抑制剂NVP-BGJ398敏感性的预测因子。在12个HNSCC细胞系中检测FGFR1的状态、表达水平和BGJ398的敏感生长。评估原发性HNSCC （n=353）的FGFR1 CNG和mRNA水平，并将HNSCC TCGA数据作为独立样本集进行查询。HNSCC pdx （n=39）接受FGFR1拷贝数检测和mRNA分析，以鉴定推定的FGFR1依赖性肿瘤。细胞系对BGJ398的敏感性与FGFR1 mRNA和蛋白水平相关，而与FGFR1 CNG无关。31%的原发性HNSCC肿瘤表达FGFR1 mRNA， 18%表达FGFR1 CNG， 35%的扩增肿瘤也表达FGFR1 mRNA阳性。TCGA数据集证实了这一关系。使用高FGFR1 mRNA进行选择，鉴定了2个HNSCC pdx，其中一个也表现出FGFR1 CNG。高mRNA水平的非扩增肿瘤在体内对BGJ398表现出敏感性。FGFR1表达与HNSCC细胞系中BGJ398敏感性相关，并预测PDXs中TKI敏感性。我们的研究结果支持FGFR1 mRNA或蛋白表达，而不是FGFR1 CNG作为HNSCC患者对FGFR抑制剂反应的预测性生物标志物。
FGFR1 copy number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors and patient-derived xenografts (PDXs) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398. FGFR1 status, expression levels and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n=353) were assessed for FGFR1 CNG and mRNA levels and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n=39) were submitted to FGFR1 copy number detection and mRNA assays to identify putative FGFR1-dependent tumors. Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. 31% of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The non-amplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398. FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts TKI sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC.