Kotani H, Ebi H, Kitai H, Nanjo S, Kita K, Huynh T G, Ooi A, Faber A C, Mino-Kenudson M, Yano S
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
Oncogene. 2016 Jul 7;35(27):3587-97. doi: 10.1038/onc.2015.426. Epub 2015 Nov 9.
Targeted therapies are effective in subsets of lung cancers with EGFR mutations and anaplastic lymphoma kinase (ALK) translocations. Large-scale genomics have recently expanded the lung cancer landscape with FGFR1 amplification found in 10-20% of squamous cell carcinomas (SCCs). However, the response rates have been low for biomarker-directed fibroblast growth factor receptor (FGFR) inhibitor therapy in SCC, which contrasts to the relatively high rates of response seen in EGFR mutant and ALK-translocated lung cancers treated with epidermal growth factor receptor (EGFR) inhibitors and ALK inhibitors, respectively. In order to better understand the low response rates of FGFR1-amplified lung cancers to FGFR inhibitors, relationships between gene copy number, mRNA expression and protein expression of FGFR1 were assessed in cell lines, tumor specimens and data from The Cancer Genome Atlas. The importance of these factors for the sensitivity to FGFR inhibitors was determined by analyzing drug screen data and conducting in vitro and in vivo experiments. We report that there was a discrepancy between FGFR1 amplification level and FGFR1 protein expression in a number of these cell lines, and the cancers with unexpectedly low FGFR1 expression were uniformly resistant to the different FGFR inhibitors. Further interrogation of the receptor tyrosine kinase activity in these discordant cell lines revealed co-activation of HER2 and platelet-derived growth factor receptor-α (PDGFRα) caused by gene amplification or ligand overexpression maintained phosphoinositide 3-kinase (PI3K) and MEK/ERK signaling even in the presence of FGFR inhibitor. Accordingly, co-inhibition of FGFR1 and HER2 or PDGFRα led to enhanced drug responses. In contrast, FGFR1-amplified high FGFR1 protein-expressing lung cancers are sensitive to FGFR inhibitor monotherapy by downregulating ERK signaling. Addition of a PI3K inhibitor to these high FGFR1 protein-expressing cancers further sensitized them to FGFR inhibitor. These data reveal that biomarker-directed trials for FGFR1-amplified SCC require assessment of FGFR1 protein expression and uncover novel therapeutic strategies for FGFR1-amplified SCC with low FGFR1 protein expression.
靶向治疗对具有表皮生长因子受体（EGFR）突变和间变性淋巴瘤激酶（ALK）易位的部分肺癌有效。大规模基因组学研究最近拓展了肺癌的研究视野，在10%-20%的肺鳞状细胞癌（SCC）中发现了成纤维细胞生长因子受体1（FGFR1）扩增。然而，生物标志物导向的成纤维细胞生长因子受体（FGFR）抑制剂治疗在SCC中的缓解率较低，这与分别用表皮生长因子受体（EGFR）抑制剂和ALK抑制剂治疗的EGFR突变型和ALK易位型肺癌中相对较高的缓解率形成对比。为了更好地理解FGFR1扩增的肺癌对FGFR抑制剂缓解率低的原因，我们在细胞系、肿瘤标本以及来自癌症基因组图谱的数据中评估了FGFR1的基因拷贝数、mRNA表达和蛋白表达之间的关系。通过分析药物筛选数据以及进行体外和体内实验，确定了这些因素对FGFR抑制剂敏感性的重要性。我们报告称，在许多这些细胞系中，FGFR1扩增水平与FGFR1蛋白表达之间存在差异，并且FGFR1表达意外低的癌症对不同的FGFR抑制剂均具有抗性。对这些不一致的细胞系中受体酪氨酸激酶活性的进一步研究表明，基因扩增或配体过表达导致的HER2和血小板衍生生长因子受体-α（PDGFRα）的共激活，即使在存在FGFR抑制剂的情况下也能维持磷脂酰肌醇3激酶（PI3K）和MEK/ERK信号传导。因此，FGFR1与HER2或PDGFRα的联合抑制导致药物反应增强。相比之下，FGFR1扩增且FGFR1蛋白高表达的肺癌通过下调ERK信号传导对FGFR抑制剂单药治疗敏感。在这些FGFR1蛋白高表达的癌症中添加PI3K抑制剂可进一步增强它们对FGFR抑制剂的敏感性。这些数据表明，针对FGFR1扩增的SCC进行的生物标志物导向试验需要评估FGFR1蛋白表达，并为FGFR1蛋白表达低的FGFR1扩增的SCC揭示新的治疗策略。
