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Ribonuclease 7-driven activation of ROS1 is a potential therapeutic target in hepatocellular carcinoma
Chunxiao Liu1, Zhengyu Zha1, Chenhao Zhou2
1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Background & Aims:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Lay Summary:
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.
Insights
Hepatocellular carcinoma (HCC) treatment is limited, but RNase7 acts as a ligand to activate ROS1 signaling. Targeting ROS1 with inhibitors may offer a new therapeutic strategy for HCC patients with high RNase7 levels.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Limited therapeutic options exist for advanced hepatocellular carcinoma (HCC).
- Receptor tyrosine kinases, like ROS1, are implicated in cancer, but ROS1's ligand was previously unidentified.
- Understanding ROS1's role is crucial for developing targeted therapies for HCC.
Purpose of the Study:
- To investigate the pathophysiological role of ROS1 in HCC.
- To identify the ligand for ROS1 and assess its therapeutic potential in HCC.
- To evaluate ROS1-targeted therapy for HCC treatment.
Main Methods:
- Purified recombinant ribonucleases (RNases) and validated the RNase7-ROS1 interaction using biochemical assays.
- Predicted protein-protein interactions between ROS1 and RNase7.
- Assessed RNase7's oncogenic function in vitro and in vivo, and evaluated anti-ROS1 inhibitor efficacy in patient-derived xenograft models.
Main Results:
- RNase7 was identified as a high-affinity ligand for ROS1, promoting oncogenic transformation.
- Elevated plasma RNase7 levels were observed in HCC patients, correlating with poor prognosis.
- ROS1 inhibitor treatment suppressed RNase7-induced tumorigenesis and reduced tumor size in preclinical models.
Conclusions:
- RNase7 functions as a ligand that activates ROS1 signaling in HCC.
- Plasma RNase7 can serve as a biomarker for identifying HCC patients suitable for anti-ROS1 therapy.
- Targeting ROS1 with inhibitors presents a promising therapeutic strategy for HCC.
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