crizotinib and Carcinoma--Hepatocellular

Among cancer-related deaths worldwide, hepatocellular carcinoma (HCC) ranks second. The hypervascular feature of most HCC underlines the importance of angiogenesis in therapy. This study aimed to identify the key genes which could characterize the angiogenic molecular features of HCC and further explore therapeutic targets to improve patients' prognosis. Public RNAseq and clinical data are from TCGA, ICGC, and GEO. Angiogenesis-associated genes were downloaded from the GeneCards database. Then, we used multi-regression analysis to generate a risk score model. This model was trained on the TCGA cohort (n = 343) and validated on the GEO cohort (n = 242). The predicting therapy in the model was further evaluated by the DEPMAP database. We developed a fourteen-angiogenesis-related gene signature that was distinctly associated with overall survival (OS). Through the nomograms, our signature was proven to possess a better predictive role in HCC prognosis. The patients in higher-risk groups displayed a higher tumor mutation burden (TMB). Interestingly, our model could group subsets of patients with different sensitivities to immune checkpoint inhibitors (ICIs) and Sorafenib. We also predicted that Crizotinib, an anti-angiogenic drug, might be more sensitive to these patients with high-risk scores by the DEPMAP. The inhibitory effect of Crizotinib in human vascular cells was obvious in vitro and in vivo. This work established a novel HCC classification based on the gene expression values of angiogenesis genes. Moreover, we predicted that Crizotinib might be more effective in the high-risk patients in our model.

Topics: Angiogenesis Inhibitors; Biomarkers, Tumor; Carcinoma, Hepatocellular; Crizotinib; Humans; Liver Neoplasms; Sorafenib

Long interspersed nuclear element 1 (LINE-1 or L1) is a dominant non-long terminal repeat (non-LTR) retrotransposon in the human genome that has been implicated in the overexpression of MET. Both the canonical MET and L1-MET transcripts are considered to play a role in hepatocellular carcinoma (HCC) development. The aim of this study was to assess the utility of canonical MET, L1-MET, and MET protein expressions as predictive biomarkers for chemo-sensitivity to MET-inhibitors in HCC cell lines in vitro. Additionally, we assessed their expression in tumour tissues from Egyptian HCC patients.. MET and L1-MET expressions were assessed by qRT-PCR in six liver cancer cell lines (SNU-387, SNU-475, SK-HEP-1, PLC/PRF/5, SNU-449 and SNU-423) and 47 HCC tumour tissues. MET protein expression was measured by western blot in cell lines and immunohistochemistry in the tumours. Cell proliferation assay was used to assess the effect of crizotinib and tivantinib on the six liver cancer cell lines in correlation with the expression of MET, L1-MET and MET.. The antitumor effect of crizotinib and tivantinib correlated with MET gene expression but not with L1-MET transcript or MET protein expressions. No significant difference was observed between HCC tumours and non-tumour samples in MET and L1-MET transcripts expression. There were no significant correlations between the 2-year overall survival rate and the MET, L1-MET transcripts and the MET protein expression.. MET RNA expression could be useful biomarker for tivantinib and crizotinib targeted therapy in HCC. The value of assessment of MET protein expression is limited.

Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Proliferation; Crizotinib; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Tumor Cells, Cultured

There are currently limited therapeutic options for hepatocellular carcinoma (HCC), particularly when it is diagnosed at advanced stages. Herein, we examined the pathophysiological role of ROS1 and assessed the utility of ROS1-targeted therapy for the treatment of HCC.. Recombinant ribonucleases (RNases) were purified, and the ligand-receptor relationship between RNase7 and ROS1 was validated in HCC cell lines by Duolink, immunofluorescence, and immunoprecipitation assays. Potential interacting residues between ROS1 and RNase7 were predicted using a protein-protein docking approach. The oncogenic function of RNase7 was analyzed by cell proliferation, migration and invasion assays, and a xenograft mouse model. The efficacy of anti-ROS1 inhibitor treatment was evaluated in patient-derived xenograft (PDX) and orthotopic models. Two independent patient cohorts were analyzed to evaluate the pathological relevance of RNase7/ROS1.. RNase7 associated with ROS1's N3-P2 domain and promoted ROS1-mediated oncogenic transformation. Patients with HCC exhibited elevated plasma RNase7 levels compared with healthy individuals. High ROS1 and RNase7 expression were strongly associated with poor prognosis in patients with HCC. In both HCC PDX and orthotopic mouse models, ROS1 inhibitor treatment markedly suppressed RNase7-induced tumorigenesis, leading to decreased plasma RNase7 levels and tumor shrinkage in mice.. RNase7 serves as a high-affinity ligand for ROS1. Plasma RNase7 could be used as a biomarker to identify patients with HCC who may benefit from anti-ROS1 treatment.. Receptor tyrosine kinases are known to be involved in tumorigenesis and have been targeted therapeutically for a number of cancers, including hepatocellular carcinoma. ROS1 is the only such receptor with kinase activity whose ligand has not been identified. Herein, we show that RNase7 acts as a ligand to activate ROS1 signaling. This has important pathophysiological and therapeutic implications. Anti-ROS1 inhibitors could be used to treatment patients with hepatocellular carcinoma and high RNase7 levels.

Topics: Animals; Biomarkers, Tumor; Carcinogenesis; Carcinoma, Hepatocellular; Cell Migration Assays; Cell Proliferation; Crizotinib; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Ligands; Liver Neoplasms; Mice; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Ribonucleases; Xenograft Model Antitumor Assays

Our study was to examine the roles of crizotinib and ceritinib in hepatocellular carcinoma (HCC) cells and explore the possible mechanisms. MTT assay was employed to examine the proliferation of five HCC cell lines treated with various concentrations of crizotinib or ceritinib. HepG2 and HCCLM3 cells were incubated with 2 nmol/l ceritinib for 1 week, followed by crystal violet staining and cell counting. Protein amounts of t-ALK, p-ALK, t-AKT, p-AKT, t-ERK, p-ERK, Mcl-1, survivin, and XIAP in HepG2 cells under different culture conditions were evaluated by western blot. HepG2 and HCCLM3 cells were treated with vehicle or ceritinib and measured by flow cytometry apoptosis analysis with Annexin-V/propidium iodide staining. MTT assay showed that both crizotinib and ceritinib suppressed the proliferation of various human HCC cells. Crystal violet staining analysis also indicated that ceritinib effectively inhibited human HCC cell proliferation. Western blot analysis indicated that both crizotinib and ceritinib inhibited ALK, AKT, and ERK phosphorylations. In addition, ceritinib reduced antiapoptotic gene expressions in HepG2 cells. Flow cytometry analysis indicated that ceritinib induced HepG2 and HCCLM3 cells apoptosis. ALK inhibitor exhibited antitumor effects by inhibiting ALK activation, repressing AKT and ERK pathways, and suppressing antiapoptotic gene expressions, which subsequently promoted apoptosis and suppressed HCC cell proliferations.

Topics: Anaplastic Lymphoma Kinase; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Crizotinib; Extracellular Signal-Regulated MAP Kinases; Hep G2 Cells; Humans; Liver Neoplasms; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Sulfones; Survivin; X-Linked Inhibitor of Apoptosis Protein