Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy
Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy
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DOI：
10.5117/9789089649362
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发表时间：
2018-10-01
期刊：
影响因子：
30.8
通讯作者：
Nam, Do-Hyun
中科院分区：
文献类型：
--
作者：
Lee, Jin-Ku;Liu, Zhaoqi;Nam, Do-Hyun
由于不同的遗传和分子背景，抗癌治疗的结果在患者中差异很大，突出了广泛的肿瘤间异质性。精确肿瘤学的基本原则定义了肿瘤的分子特征，以指导最佳的患者定制治疗。为了实现这一目标，我们已经建立了14种癌症类型的462个患者源性肿瘤细胞（PDC）的药理学景观汇编，以及其中385个肿瘤的基因组和转录组学分析。与传统的长期培养的肿瘤细胞系模型相比，PDCs能更准确地再现肿瘤的分子生物学特性。在这里，我们提供了对动态药物基因组学关联的见解，包括引起EGFR抑制剂治疗耐药性的分子决定因素，以及伊曲替尼（目前用于血液恶性肿瘤）用于胶质瘤EGFR特异性治疗的潜在再利用。最后，我们提出了一个潜在的实现的PDC衍生的药物敏感性的预测临床反应的靶向治疗，使用回顾性临床研究。
Outcomes of anticancer therapy vary dramatically among patients due to diverse genetic and molecular backgrounds, highlighting extensive intertumoral heterogeneity. The fundamental tenet of precision oncology defines molecular characterization of tumors to guide optimal patient-tailored therapy. Towards this goal, we have established a compilation of pharmacological landscapes of 462 patient-derived tumor cells (PDCs) across 14 cancer types, together with genomic and transcriptomic profiling in 385 of these tumors. Compared with the traditional long-term cultured cancer cell line models, PDCs recapitulate the molecular properties and biology of the diseases more precisely. Here, we provide insights into dynamic pharmacogenomic associations, including molecular determinants that elicit therapeutic resistance to EGFR inhibitors, and the potential repurposing of ibrutinib (currently used in hematological malignancies) for EGFR-specific therapy in gliomas. Lastly, we present a potential implementation of PDC-derived drug sensitivities for the prediction of clinical response to targeted therapeutics using retrospective clinical studies.