Research on the role of c-Myc in liver cancer therapy and drug resistance using cell line and organoid models
10.12354/j.issn.1000-8179.2024.20240411
- VernacularTitle:基于细胞系和类器官研究c-Myc在肝癌治疗和耐药中的作用
- Author:
Cheng JINGHUI
1
;
Qin YIXUAN
;
Yang HUI
Author Information
1. 北京大学第一医院肿瘤转化研究中心(北京市 100034)
- Keywords:
liver cancer;
c-Myc;
drug resistance
- From:
Chinese Journal of Clinical Oncology
2024;51(8):385-391
- CountryChina
- Language:Chinese
-
Abstract:
To investigate the potential therapeutic effects of the myelocytomatosis oncogene(c-Myc)using pharmacogenomic data from liv-er cancer cell lines and organoids.Methods:Drug sensitivity,functional genomics,and gene expression data from cell lines were collected to assess the correlation between the expression of c-Myc and drug sensitivity.Differential expression and prognostic relevance of c-Myc in a primary liver cancer cohort were analyzed.Immunohistochemistry(IHC)staining validated c-Myc expression in liver cancer patients and cor-related it with the drug sensitivity of organoids obtained from an organoid biobank.Three c-Myc inhibitors were screened on liver cancer cell lines and organoids to test tumor-killing effects in two-and three-dimensional levels.Bioinformatics analysis was conducted to explore the role of c-Myc in targeted drug resistance.Results:Bioinformatics analyses combined with IHC staining revealed a potential regulatory role of c-Myc in the drug sensitivity of liver cancer.The expression of c-Myc in cancerous tissues was significantly higher than in para-cancerous tis-sues,and c-Myc expression was higher in patients resistant to targeted drugs than in those sensitive to targeted drugs(P<0.05).Drug screening experiments showed that c-Myc inhibitors including THZ1,ABBV-744,and JQ1 reduced cell viability in both tumor cells and tumor organoids.The combination of lenvatinib and c-Myc inhibitors exhibited significant synergistic effects(all synergy scores>1)in the SNU-739 cell line.Analysis of organoids from an organoid biobank indicated a strong association between c-Myc and stemness-mediated targeted drug resistance(R=0.87).Conclusions:c-Myc showed increased expression in patients resistant to targeted therapy,suggesting it as a novel target for drugs in liver cancer.Inhibition of c-Myc effectively killed tumors in both two-and three-dimensional ex vivo models.
