基于患者来源的细胞的药物基因组学评估，以揭示晚期肺癌的潜在耐药机制和新的治疗方法。
Patient-derived cell-based pharmacogenomic assessment to unveil underlying resistance mechanisms and novel therapeutics for advanced lung cancer.
机构信息
Research Institute, National Cancer Center, Goyang-si, Gyeonggi-do, 10408, Republic of Korea.
Department of Precision Medicine, National Institute of Health, Korea Disease Control and Prevention Agency, Cheongju, 28159, Republic of Korea.
出版信息
J Exp Clin Cancer Res. 2023 Jan 30;42(1):37. doi: 10.1186/s13046-023-02606-3.
BACKGROUND
A pharmacogenomic platform using patient-derived cells (PDCs) was established to identify the underlying resistance mechanisms and tailored treatment for patients with advanced or refractory lung cancer.
METHODS
Drug sensitivity screening and multi-omics datasets were acquired from lung cancer PDCs (n = 102). Integrative analysis was performed to explore drug candidates according to genetic variants, gene expression, and clinical profiles.
RESULTS
PDCs had genomic characteristics resembled with those of solid lung cancer tissues. PDC molecular subtyping classified patients into four groups: (1) inflammatory, (2) epithelial-to-mesenchymal transition (EMT)-like, (3) stemness, and (4) epithelial growth factor receptor (EGFR)-dominant. EGFR mutations of the EMT-like subtype were associated with a reduced response to EGFR-tyrosine kinase inhibitor therapy. Moreover, although RB1/TP53 mutations were significantly enriched in small-cell lung cancer (SCLC) PDCs, they were also present in non-SCLC PDCs. In contrast to its effect in the cell lines, alpelisib (a PI3K-AKT inhibitor) significantly inhibited both RB1/TP53 expression and SCLC cell growth in our PDC model. Furthermore, cell cycle inhibitors could effectively target SCLC cells. Finally, the upregulation of transforming growth factor-β expression and the YAP/TAZ pathway was observed in osimertinib-resistant PDCs, predisposing them to the EMT-like subtype. Our platform selected XAV939 (a WNT-TNKS-β-catenin inhibitor) for the treatment of osimertinib-resistant PDCs. Using an in vitro model, we further demonstrated that acquisition of osimertinib resistance enhances invasive characteristics and EMT, upregulates the YAP/TAZ-AXL axis, and increases the sensitivity of cancer cells to XAV939.
CONCLUSIONS
Our PDC models recapitulated the molecular characteristics of lung cancer, and pharmacogenomics analysis provided plausible therapeutic candidates.
背景
建立了一个使用患者来源细胞（PDC）的药物基因组学平台，以鉴定晚期或难治性肺癌患者的潜在耐药机制，并为其制定个体化治疗方案。
方法
从肺癌 PDC（n=102）中获取药物敏感性筛选和多组学数据集。根据遗传变异、基因表达和临床特征进行综合分析，以探索候选药物。
结果
PDC 具有与实体肺癌组织相似的基因组特征。PDC 分子分型将患者分为四组：（1）炎症型，（2）上皮-间质转化（EMT）样型，（3）干细胞样型，和（4）表皮生长因子受体（EGFR）主导型。EMT 样亚型的 EGFR 突变与 EGFR 酪氨酸激酶抑制剂治疗反应降低相关。此外，尽管 RB1/TP53 突变在小细胞肺癌（SCLC）PDC 中显著富集，但也存在于非 SCLC PDC 中。与在细胞系中的作用相反，阿培利司（一种 PI3K-AKT 抑制剂）在我们的 PDC 模型中显著抑制 RB1/TP53 表达和 SCLC 细胞生长。此外，细胞周期抑制剂可有效靶向 SCLC 细胞。最后，在奥希替尼耐药的 PDC 中观察到转化生长因子-β表达上调和 YAP/TAZ 通路激活，使其易向 EMT 样亚型转化。我们的平台选择 XAV939（一种 WNT-TNKS-β-catenin 抑制剂）治疗奥希替尼耐药的 PDC。通过体外模型，我们进一步证明奥希替尼耐药的获得增强了侵袭特征和 EMT，上调了 YAP/TAZ-AXL 轴，并增加了癌细胞对 XAV939 的敏感性。
结论
我们的 PDC 模型再现了肺癌的分子特征，药物基因组学分析提供了合理的治疗候选药物。
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