Precision medicine aims to tailor cancer therapies to target specific tumor-promoting aberrations. For tumors that lack actionable drivers, which occurs frequently in the clinic, extensive molecular characterization and pre-clinical drug efficacy studies will be required. A cell line maintained at low passage and a patient- derived xenograft model (PDX) were generated using a fresh biopsy from a patient with a poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation sequencing, high throughput signaling network analysis, and drug efficacy trials were then conducted to identify actionable targets for therapeutic intervention. No actionable mutations were identified after whole exome sequencing of the patient’s DNA. However, whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, that include the PIK3CA and RICTOR genes, respectively. We then conducted pathway analysis, which revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated in the tumor biopsy-derived cell culture and PDX, and response to the AKT inhibitor AZD5363 was observed both in vitro and in vivo indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. In conclusion, our study demonstrates that high throughput signaling pathway analysis will significantly aid in identifying actionable alterations in rare tumors and guide patient stratification into early-phase clinical trials.

精密医学旨在针对特定的肿瘤促进畸变量身定制癌症疗法。对于缺乏可操作的驱动因子的肿瘤（在临床上经常发生），将需要进行广泛的分子表征和临床前药物功效研究。使用新鲜活检从患有原发性来源不明的差分化神经内分泌肿瘤的患者中进行活检，产生维持低传代的细胞系和患者衍生的异种移植模型（PDX）。然后进行了下一代测序，高通量信号网络分析和药物功效试验，以鉴定可用于治疗干预的靶标。在对患者的DNA进行完整的外显子组测序后，没有发现可操作的突变。但是，全基因组测序显示3q和5p染色体臂的扩增，PIK3CA和RICTOR基因分别。然后，我们进行了途径分析，揭示了AKT途径的激活。基于此分析，在肿瘤活检衍生的细胞培养物和PDX中评估了PIK3CA和AKT抑制剂的功效，并在体内和体外观察到了对AKT抑制剂AZD5363的反应，表明该患者将受益于针对肿瘤的靶向治疗丝氨酸/苏氨酸激酶AKT。总之，我们的研究表明，高通量信号通路分析将显着帮助鉴定罕见肿瘤中的可行变化，并指导患者分层进入早期临床试验。