The MST1R/RON Tyrosine Kinase in Cancer: Oncogenic Functions and Therapeutic Strategies

SIMPLE SUMMARY: MST1R/RON receptor tyrosine kinase is a highly conserved transmembrane protein present on epithelial cells, macrophages, and recently identified in a T-cell subset. RON activation attenuates inflammation in healthy tissue. Interestingly, it is overexpressed in several epithelial neoplasms with increasing levels of expression associated with worse outcomes. Though the mechanisms involved are still under investigation, RON is involved in carcinogenesis via immune modulation of the immune tumor microenvironment, activation of numerous oncogenic pathways, and is protective under cellular stress. Alternatively, inhibition of RON abrogates tumor progression in both animal and human tissue models. Given this, RON is a targetable protein of great interest for cancer treatment. Here, we review RON’s function in tissue inflammation and cancer progression, and review cancer clinical trials to date that have used agents targeting RON signaling. ABSTRACT: The MST1R/RON receptor tyrosine kinase is a homologue of the more well-known MET receptor. Like MET, RON orchestrates cell signaling pathways that promote oncogenesis and enable cancer cell survival; however, it has a more unique role in the regulation of inflammation. RON was originally described as a transmembrane receptor expressed on tissue resident macrophages and various epithelial cells. RON is overexpressed in a variety of cancers and its activation modifies multiple signaling pathways with resultant changes in epithelial and immune cells which together modulate oncogenic phenotypes. While several RON isoforms have been identified with differences in structure, activation, and pathway regulation, increased RON expression and/or activation is consistently associated with worse outcomes. Tyrosine kinase inhibitors targeting RON have been developed, making RON an actionable therapeutic target.