RON in hepatobiliary and pancreatic cancers: Pathogenesis and potential therapeutic targets

Abstract

The receptor protein tyrosine kinase RON belongs to the c-MET proto-oncogene family. Research has shown that RON has a role in cancer pathogenesis, which places RON on the frontline of the development of novel cancer therapeutic strategies. Hepatobiliary and pancreatic (HBP) cancers have a poor prognosis, being reported as having higher rates of cancer-related death. Therefore, to combat these malignant diseases, the mechanism underlying the aberrant expression and signaling of RON in HBP cancer pathogenesis, and the development of RON as a drug target for therapeutic intervention should be investigated. Abnormal RON expression and signaling have been identified in HBP cancers, and also act as tumorigenic determinants for HBP cancer malignant behaviors. In addition, RON is emerging as an important mediator of the clinical prognosis of HBP cancers. Thus, not only is RON significant in HBP cancers, but also RON-targeted therapeutics could be developed to treat these cancers, for example, therapeutic monoclonal antibodies and small-molecule inhibitors. Among them, antibody-drug conjugates have become increasingly popular in current research and their potential as novel anti-cancer biotherapeutics will be determined in future clinical trials.

Keywords: Hepatobiliary; Molecular targeted therapy; Pancreatic neoplasms; RON; Signal transduction.

Figure 1

Mechanisms of RON activation and downstream signaling pathways. Classically, macrophage-stimulating protein (MSP) activates RON. In cancer, RON activation is induced by overexpression, splicing or truncation, and transactivation. The RON receptor consists of three regions including the extracellular domain, the transmembrane domain, as well as the intracellular domain. MSP binding to the extracellular domain leads to autophosphorylation of several tyrosine residues in the kinase activation loop or in the C-terminal tail, resulting in the activation of many biological activities, including increased proliferation/survival, motile-invasive activity, and chemoresistance. MSP: Macrophage-stimulating protein; SOS: Son of Sevenless; GRB2: Growth factor receptor-bound protein 2; CBL: Casitas B-lineage lymphoma; 14-3-3: Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein; PI-3K-AKT: Phosphatidylinositol-4,5-Bisphosphate 3 kinase- protein kinase B; HIF: Hypoxia-inducible factor; RAS-MAPK: RAS-mitogen-activated protein kinase; ERK: Extracellular regulated kinase; RSK: Ribosomal protein S6 kinase; mTOR: Mechanistic target of rapamycin.