Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China.
Laboratory of Liver Transplantation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, Chengdu, China.
Front Immunol. 2022 Oct 7;13:990571. doi: 10.3389/fimmu.2022.990571. eCollection 2022.
Molecular targeted therapy has shown potential in hepatocellular carcinoma (HCC) patients, and immunotherapy applications are developing rapidly. However, clinical guidance for making individualized therapy decisions for HCC patients remains lacking. MDH (Medication Decision in HCC) gene signatures comprising 70 genes were screened using transcriptomic data from multikinase inhibitor (TKI)-resistant HCC cells and HCC patient-derived xenograft model (PDX) models. Four MDH subtypes with distinct biological and clinical characteristics were defined by unsupervised cluster analysis of HCC data from The Cancer Genome Atlas (TCGA) database. To facilitate individualized and reasonable clinical guidance for each HCC patient, we constructed the MDH score. Comprehensive analysis suggested high MDH scores were associated with TKI resistance, a high proportion of stromal cell infiltration and poor survival outcomes. We recommend concomitant stromal activity intervention and immunotherapy for this type of HCC. Moreover, low MDH scores indicate TKI sensitivity, and a combination of targeted and immunotherapy is recommended. The nomogram constructed by iteration least absolute shrinkage and selection operator (LASSO) Cox regression analysis successfully predicted 3- or 5-year survival outcomes and mortality risks of HCC patients. In conclusion, TKI resistance model-based MDH gene signatures provide novel insight into potential mechanisms of drug resistance and heterogeneity in HCC. Integrative analysis plus a simplified decision model may aid personalized treatment and prognostic assessment among HCC patients.
分子靶向治疗在肝细胞癌（HCC）患者中显示出潜力，免疫治疗应用也在迅速发展。然而，对于 HCC 患者制定个体化治疗决策的临床指导仍然缺乏。使用多激酶抑制剂（TKI）耐药 HCC 细胞和 HCC 患者来源异种移植模型（PDX）模型的转录组数据筛选了包含 70 个基因的 MDH（HCC 药物决策）基因特征。通过对 TCGA 数据库中的 HCC 数据进行无监督聚类分析，定义了具有不同生物学和临床特征的 4 种 MDH 亚型。为了为每个 HCC 患者提供个体化和合理的临床指导，我们构建了 MDH 评分。综合分析表明，高 MDH 评分与 TKI 耐药、基质细胞浸润比例高和生存结局不良相关。我们建议对此类 HCC 进行联合基质活性干预和免疫治疗。此外，低 MDH 评分表明 TKI 敏感性，建议联合靶向和免疫治疗。迭代最小绝对收缩和选择算子（LASSO）Cox 回归分析构建的列线图成功预测了 HCC 患者的 3 年或 5 年生存结局和死亡风险。总之，基于 TKI 耐药模型的 MDH 基因特征为 HCC 药物耐药和异质性的潜在机制提供了新的见解。综合分析加简化决策模型可能有助于 HCC 患者的个体化治疗和预后评估。
