Andrea Cavazzoni, Irene Salamon, Claudia Fumarola, Giulia Gallerani, Noemi Laprovitera, Francesco Gelsomino, Mattia Riefolo, Karim Rihawi, Elisa Porcellini, Tania Rossi, Martina Mazzeschi, Maria Naddeo, Salvatore Serravalle, Elisabetta Broseghini, Federico Agostinis, Olivier Deas, Roberta Roncarati, Giorgio Durante, Ilaria Pace, Mattia Lauriola, Ingrid Garajova, George A Calin, Massimiliano Bonafè, Antonia D'Errico, Pier Giorgio Petronini, Stefano Cairo, Andrea Ardizzoni, Gabriele Sales, Manuela Ferracin
{"title":"表皮生长因子受体 2 和 MEK 抑制剂在治疗表皮生长因子受体 2 扩增的原发性不明癌症中的协同活性。","authors":"Andrea Cavazzoni, Irene Salamon, Claudia Fumarola, Giulia Gallerani, Noemi Laprovitera, Francesco Gelsomino, Mattia Riefolo, Karim Rihawi, Elisa Porcellini, Tania Rossi, Martina Mazzeschi, Maria Naddeo, Salvatore Serravalle, Elisabetta Broseghini, Federico Agostinis, Olivier Deas, Roberta Roncarati, Giorgio Durante, Ilaria Pace, Mattia Lauriola, Ingrid Garajova, George A Calin, Massimiliano Bonafè, Antonia D'Errico, Pier Giorgio Petronini, Stefano Cairo, Andrea Ardizzoni, Gabriele Sales, Manuela Ferracin","doi":"10.1016/j.ymthe.2024.07.011","DOIUrl":null,"url":null,"abstract":"<p><p>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. 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引用次数: 0
摘要
原发灶不明的癌症(CUP)患者承受着侵袭性疾病和治疗机会减少的双重负担。实验模型对 CUP 的生物学研究和药物测试至关重要。我们从腹水肿瘤细胞中提取了两种 CUP 细胞系(CUP#55 和 #96)以及相应的患者来源异种移植(PDX)。我们对 CUP 细胞系和 PDX 进行了组织学、免疫表型、分子和基因组学鉴定,确认了原始肿瘤的特征。原发组织预测来自肿瘤 microRNA 表达谱,并通过单细胞转录组学得到证实。基因组检测和 FISH 分析在两个模型中都发现了 FGFR2 基因扩增,在 CUP#55 中为同源染色区(HSR),在 CUP#96 中为双分钟。FGFR2 被认为是主要的致癌驱动因素和治疗靶点。事实证明,FGFR2靶向药物BGJ-398(infigratinib)与MEK抑制剂曲美替尼(trametinib)联用具有协同作用,在体外和体内均有显著疗效。通过单细胞基因表达分析对联合治疗效果的研究发现,肿瘤细胞具有显著的可塑性,具有上皮表型的细胞对联合治疗更为敏感。这项研究使 CUP 患者更接近个性化治疗,并为 FGFR2 和 MEK 靶向治疗 FGFR2 通路激活的转移性肿瘤提供了理论依据。
Synergic activity of FGFR2 and MEK inhibitors in the treatment of FGFR2-amplified cancers of unknown primary.
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 in situ hybridization analysis identified FGFR2 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 in vitro and in vivo. 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.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.