Metastatic colorectal cancer (CRC) continues to be a major health problem, and current treatments are primarily for disease control and palliation of symptoms. In this study, we developed a precision medicine strategy to discover novel therapeutics for patients with CRC. Six matched low-passage cell lines and patient-derived xenografts (PDX) were established from CRC patients undergoing resection of their cancer. High-throughput drug screens using a 119 FDA-approved oncology drug library were performed on these cell lines, which were then validated in vivo in matched PDXs. RNA-Seq analysis was then performed to identify predictors of response. Our study revealed marked differences in response to standard-of-care agents across patients and pinpointed druggable pathways to treat CRC. Among these pathways co-targeting of fibroblast growth factor receptor (FGFR), SRC, platelet derived growth factor receptor (PDGFR), or vascular endothelial growth factor receptor (VEGFR) signaling was found to be an effective strategy. Molecular analyses revealed potential predictors of response to these druggable pathways. Our data suggests that the use of matched low-passage cell lines and PDXs is a promising strategy to identify new therapies and pathways to treat metastatic CRC.

中文翻译：

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开发精密医疗管道，以识别大肠癌的个性化治疗方法。

转移性结直肠癌（CRC）仍然是主要的健康问题，目前的治疗方法主要是控制疾病和缓解症状。在这项研究中，我们开发了一种精确的药物策略，以发现针对CRC患者的新疗法。从接受癌症切除的CRC患者中建立了六种匹配的低代细胞系和患者来源的异种移植物（PDX）。在这些细胞系上使用119种FDA批准的肿瘤药物库进行了高通量药物筛选，然后在匹配的PDX中进行了体内验证。然后进行RNA-Seq分析以鉴定反应的预测因子。我们的研究显示，患者对护理标准药物的反应存在明显差异，并指出了治疗CRC的可明确药物途径。在这些途径中，共靶向成纤维细胞生长因子受体（FGFR），SRC，血小板衍生生长因子受体（PDGFR）或血管内皮生长因子受体（VEGFR）信号被发现是一种有效的策略。分子分析揭示了对这些药物通路反应的潜在预测因子。我们的数据表明，使用匹配的低代细胞系和PDXs是一种有前途的策略，可用于鉴定治疗转移性CRC的新疗法和途径。