Pharmacogenomic profiling of intra-tumor heterogeneity by a large organoid biobank of liver cancer

Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we established a PLC biobank, consisting of 399 organoids derived from 144 patients, which recapitulated histopathology and genomic landscape of parental tumors, and were reliable for drug sensitivity screening, evidenced by both in vivo models and patient response. Integrative analysis dissected PLC heterogeneity, regarding genomic, transcriptomic characteristics and sensitivity to seven clinically-relevant drugs, as well as clinical associations. Pharmacogenomic analysis identified and validated multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, c-Jun was revealed as a major mediator to Lenvatinib resistance, through JNK and β-catenin signaling. A new compound (PKUF-01) comprising moieties of Lenvatinib and Veratramine (c-Jun inhibitor) was synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterized the landscape of PLC heterogeneity, developed predictive biomarker panels, and revealed a novel Lenvatinib resistant mechanism for combinatory therapy.

肿瘤间异质性和肿瘤内异质性是原发性肝细胞癌（PLC）精准治疗的主要障碍。本研究建立了包含399个由144名患者来源的类器官的PLC生物库，这些类器官重现了母体肿瘤的病理学和组织基因组特征，并在体内模型和患者反应中证实了其在药物敏感性筛选中的可靠性。综合分析揭示了PLC异质性，包括基因组、转录组特征以及对七种临床相关药物的敏感性，以及临床相关性。药基因组学分析鉴定并验证了多基因表达特征，这些特征可预测药物反应，从而实现更精准的患者分层。此外，c-Jun被揭示为Lenvatinib耐药性的主要介导因子，通过JNK和β-catenin信号通路。一种新的化合物（PKUF-01），由Lenvatinib和Veratramine（c-Jun抑制剂）的成分组成，已被合成并筛选，显示出显著的协同效应。总之，本研究描绘了PLC异质性的图谱，开发了预测性生物标志物面板，并揭示了Lenvatinib耐药性的新型机制，为联合治疗提供了新的策略。