Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity
Phenotypic profiling with a living biobank of primary rhabdomyosarcoma unravels disease heterogeneity and AKT sensitivity
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DOI：
10.1038/s41467-020-18388-7
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发表时间：
2020-09-15
影响因子：
16.6
通讯作者：
Wachtel, Marco
中科院分区：
文献类型：
--
作者：
Manzella, Gabriele;Schreck, Leonie D.;Wachtel, Marco
癌症治疗目前正在从广泛使用的细胞毒性药物转向患者特异性精确治疗。通过分子分析鉴定的可药物化的驱动癌基因仅存在于一部分患者中。原发性肿瘤细胞的功能分析可以规避这些限制，但对于大多数癌症实体来说，合适的平台是不可用的。在这里，我们描述了一个横纹肌肉瘤（RMS）的体外药物分析平台，使用由20个RMS患者来源的异种移植物（PDX）组成的活体生物库进行高通量药物测试。优化的体外条件保留了原代PDX细胞的表型和分子特征，并且与直接从患者肿瘤分离的细胞的增殖相容。除了主要针对患者特异性脆弱性的反应的异质谱之外，用大型药物库进行的分析揭示了RMS亚组中对AKT抑制剂的强烈敏感性。总的来说，我们的研究强调了原发性RMS体外药物分析在联合临床环境中用于患者特异性治疗选择的可行性。
Cancer therapy is currently shifting from broadly used cytotoxic drugs to patient-specific precision therapies. Druggable driver oncogenes, identified by molecular analyses, are present in only a subset of patients. Functional profiling of primary tumor cells could circumvent these limitations, but suitable platforms are unavailable for most cancer entities. Here, we describe an in vitro drug profiling platform for rhabdomyosarcoma (RMS), using a living biobank composed of twenty RMS patient-derived xenografts (PDX) for high-throughput drug testing. Optimized in vitro conditions preserve phenotypic and molecular characteristics of primary PDX cells and are compatible with propagation of cells directly isolated from patient tumors. Besides a heterogeneous spectrum of responses of largely patient-specific vulnerabilities, profiling with a large drug library reveals a strong sensitivity towards AKT inhibitors in a subgroup of RMS. Overall, our study highlights the feasibility of in vitro drug profiling of primary RMS for patient-specific treatment selection in a co-clinical setting.