BACKGROUND The fibroblast growth factor receptor (FGFR) signaling pathway is activated in multiple tumor types through gene amplifications, single base substitutions, or gene fusions. Multiple small molecule kinase inhibitors targeting FGFR are currently being evaluated in clinical trials for patients with FGFR chromosomal translocations. Patients with novel gene fusions involving FGFR may represent candidates for kinase inhibitors. METHODS A targeted RNA-sequencing assay identified a KLK2-FGFR2 fusion gene in two patients with metastatic prostate cancer. NIH3T3 cells were transduced to express the KLK2-FGFR2 fusion. Migration assays, Western blots, and drug sensitivity assays were performed to functionally characterize the fusion. RESULTS Expression of the KLK2-FGFR2 fusion protein in NIH3T3 cells induced a profound morphological change promoting enhanced migration and activation of downstream proteins in FGFR signaling pathways. The KLK2-FGFR2 fusion protein was determined to be highly sensitive to the selective FGFR inhibitors AZD-4547, BGJ398, JNJ-42756943, the irreversible inhibitor TAS-120, and the non-selective inhibitor Ponatinib. The KLK2-FGFR2 fusion did not exhibit sensitivity to the non-selective inhibitor Dovitinib. CONCLUSIONS Importantly, the KLK2-FGFR2 fusion represents a novel target for precision therapies and should be screened for in men with prostate cancer.

中文翻译：

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两例转移性前列腺癌中 KLK2-FGFR2 融合基因的表征。

背景技术成纤维细胞生长因子受体（FGFR）信号通路在多种肿瘤类型中通过基因扩增、单碱基取代或基因融合被激活。目前正在针对 FGFR 染色体易位患者的临床试验中评估多种靶向 FGFR 的小分子激酶抑制剂。具有涉及 FGFR 的新基因融合的患者可能代表激酶抑制剂的候选者。方法 靶向 RNA 测序分析在两名转移性前列腺癌患者中鉴定出 KLK2-FGFR2 融合基因。NIH3T3 细胞被转导以表达 KLK2-FGFR2 融合。进行迁移测定、蛋白质印迹和药物敏感性测定以在功能上表征融合。结果 KLK2-FGFR2 融合蛋白在 NIH3T3 细胞中的表达诱导了深刻的形态学变化，促进了 FGFR 信号通路中下游蛋白的迁移和活化。KLK2-FGFR2 融合蛋白被确定为对选择性 FGFR 抑制剂 AZD-4547、BGJ398、JNJ-42756943、不可逆抑制剂 TAS-120 和非选择性抑制剂 Ponatinib 高度敏感。KLK2-FGFR2 融合对非选择性抑制剂 Dovitinib 没有表现出敏感性。结论 重要的是，KLK2-FGFR2 融合代表了精准治疗的新靶点，应该在患有前列腺癌的男性中进行筛查。BGJ398、JNJ-42756943、不可逆抑制剂TAS-120和非选择性抑制剂Ponatinib。KLK2-FGFR2 融合对非选择性抑制剂 Dovitinib 没有表现出敏感性。结论 重要的是，KLK2-FGFR2 融合代表了精准治疗的新靶点，应该在患有前列腺癌的男性中进行筛查。BGJ398、JNJ-42756943、不可逆抑制剂TAS-120和非选择性抑制剂Ponatinib。KLK2-FGFR2 融合对非选择性抑制剂 Dovitinib 没有表现出敏感性。结论 重要的是，KLK2-FGFR2 融合代表了精准治疗的新靶点，应该在患有前列腺癌的男性中进行筛查。