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Targeting RON receptor tyrosine kinase for treatment of advanced solid cancers: antibody–drug conjugates as lead drug candidates for clinical trials

Authors :
Hang-Ping Yao
Sreedhar Reddy Suthe
Xiang-Min Tong
Ming-Hai Wang
Source :
Therapeutic Advances in Medical Oncology, Vol 12 (2020)
Publication Year :
2020
Publisher :
SAGE Publishing, 2020.

Abstract

The recepteur d’origine nantais (RON) receptor tyrosine kinase, belonging to the mesenchymal-to-epithelial transition proto-oncogene family, has been implicated in the pathogenesis of cancers derived from the colon, lung, breast, and pancreas. These findings lay the foundation for targeting RON for cancer treatment. However, development of RON-targeted therapeutics has not gained sufficient attention for the last decade. Although therapeutic monoclonal antibodies (TMABs) targeting RON have been validated in preclinical studies, results from clinical trials have met with limited success. This outcome diminishes pharmaceutical enthusiasm for further development of RON-targeted therapeutics. Recently, antibody–drug conjugates (ADCs) targeting RON have drawn special attention owing to their increased therapeutic activity. The rationale for developing anti-RON ADCs is based on the observation that cancer cells are not sufficiently addicted to RON signaling for survival. Thus, TMAB-mediated inhibition of RON signaling is ineffective for clinical application. In contrast, anti-RON ADCs combine a target-specific antibody with potent cytotoxins for cancer cell killing. This approach not only overcomes the shortcomings in TMAB-targeted therapies but also holds the promise for advancing anti-RON ADCs into clinical trials. In this review, we discuss the latest advancements in the development of anti-RON ADCs for targeted cancer therapy including drug conjugation profile, pharmacokinetic properties, cytotoxic effect in vitro , efficacy in tumor models, and toxicological activities in primates.

Details

Language :
English
ISSN :
17588359
Volume :
12
Database :
Directory of Open Access Journals
Journal :
Therapeutic Advances in Medical Oncology
Publication Type :
Academic Journal
Accession number :
edsdoj.52750e765a9648fcb2060448bb091321
Document Type :
article
Full Text :
https://doi.org/10.1177/1758835920920069