Ribonuclease 7-driven activation of ROS1 is a potential therapeutic target in hepatocellular carcinoma

• Published in: Journal of hepatology Vol. 74; no. 4; pp. 907 - 918
• Main Authors: Liu, Chunxiao, Zha, Zhengyu, Zhou, Chenhao, Chen, Yeh, Xia, Weiya, Wang, Ying-Nai, Lee, Heng-Huan, Yin, Yirui, Yan, Meisi, Chang, Chiung-Wen, Chan, Li-Chuan, Qiu, Yufan, Li, Hui, Li, Chia-Wei, Hsu, Jung-Mao, Hsu, Jennifer L., Wang, Shao-Chun, Ren, Ning, Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-04-2021; Elsevier Science Ltd
• Subjects: Animal models; Animals; Biomarkers, Tumor - metabolism; Cancer; Carcinogenesis - drug effects; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell migration; Cell Migration Assays - methods; Cell proliferation; Cell Proliferation - drug effects; Crizotinib; Crizotinib - pharmacology; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - drug effects; Hepatocellular carcinoma; Humans; Immunofluorescence; Immunoprecipitation; Kinases; Ligands; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Mice; Patients; Plasma biomarker; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Ribonuclease 7; Ribonucleases - metabolism; ROS1; Signaling; Therapeutic targets; Treatment stratification; Tumorigenesis; Tyrosine; Tyrosine kinase; Xenograft Model Antitumor Assays; Xenografts; Crizotinib; Treatment stratification; Tyrosine kinase; Signaling; Plasma biomarker; Hepatocellular carcinoma; Ribonuclease 7; ROS1; Cancer
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2020.09.030

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.
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•High RNase7 levels are positively correlated with poor prognosis in patients with HCC.•RNase7 acts as a ligand by binding and interacting with its receptor ROS1.•RNase7-mediated ROS1 activation triggers oncogenic transformation.•High plasma RNase7 levels can be used to stratify patients who will benefit from anti-ROS1 inhibitors.