Patients with cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies. Experimental models are pivotal for CUP biology investigation and drug testing. We derived two CUP cell lines (CUP#55 and #96) and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines and PDXs underwent histological, immune-phenotypical, molecular, and genomic characterization confirming the features of the original tumor. The tissue-of-origin prediction was obtained from the tumor microRNA expression profile and confirmed by single-cell transcriptomics. Genomic testing and fluorescence hybridization analysis identified gene amplification in both models, in the form of homogeneously staining region (HSR) in CUP#55 and double minutes in CUP#96. FGFR2 was recognized as the main oncogenic driver and therapeutic target. FGFR2-targeting drug BGJ398 (infigratinib) in combination with the MEK inhibitor trametinib proved to be synergic and exceptionally active, both and . The effects of the combined treatment by single-cell gene expression analysis revealed a remarkable plasticity of tumor cells and the greater sensitivity of cells with epithelial phenotype. This study brings personalized therapy closer to CUP patients and provides the rationale for FGFR2 and MEK targeting in metastatic tumors with FGFR2 pathway activation.

中文翻译：

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FGFR2 和 MEK 抑制剂在治疗原发灶不明的 FGFR2 扩增癌症中的协同活性


原发灶不明的癌症 (CUP) 患者承受着侵袭性疾病和获得治疗机会减少的双重负担。实验模型对于 CUP 生物学研究和药物测试至关重要。我们从腹水肿瘤细胞中衍生出两种 CUP 细胞系（CUP#55 和 #96）以及相应的患者来源的异种移植物 (PDX)。 CUP 细胞系和 PDX 进行了组织学、免疫表型、分子和基因组表征，证实了原始肿瘤的特征。组织起源预测是从肿瘤 microRNA 表达谱中获得的，并通过单细胞转录组学证实。基因组测试和荧光杂交分析识别了两种模型中的基因扩增，其形式为 CUP#55 中的均质染色区域 (HSR) 和 CUP#96 中的双分钟。 FGFR2 被认为是主要的致癌驱动因素和治疗靶点。 FGFR2 靶向药物 BGJ398（infigratinib）与 MEK 抑制剂曲美替尼（Trametinib）联合使用被证明具有协同作用且异常活跃。通过单细胞基因表达分析联合治疗的效果揭示了肿瘤细胞显着的可塑性以及具有上皮表型的细胞更高的敏感性。这项研究使个性化治疗更贴近 CUP 患者，并为 FGFR2 通路激活的转移性肿瘤中的 FGFR2 和 MEK 靶向治疗提供了理论基础。