Chapter 21 - Receptor tyrosine kinase-like orphan receptors ROR1/2: Insights into the mechanism of action, inhibition, and therapeutic potential

Abstract

Targeted molecular therapy provides a new opportunity for treating different types of cancers. Cellular protein expression is vital for such targeted therapies. Receptortyrosine kinases (RTKs) are the most potential targets for cancer therapies. Transmembrane RTKs such as receptor tyrosine kinase-like orphan receptors (ROR) are absent in normal tissues but found in human cancers, contributing to tumor growth, migration, and invasion. Specific and tumor-restricted expression profiles of these receptors offer an exceptionally unique therapeutic targeting approach for human cancer. Targeting evolutionarily conserved ROR1 and ROR2 by small molecule inhibitors and monoclonal antibodies serves as a promising cancer therapeutic target. ROR1 and ROR2 are involved in noncanonical Wnt signaling as Wnt5a receptors in metastatic cancers and organogenesis. ROR1 is the hallmark for many cancers and is critically linked with solid and blood cancer progression. Current evidence reveals the furthermore involvement of ROR2 as a Wnt ligand-receptor in canonical Wnt signaling. High expression is correlated with the most aggressive cancer. Further studies to understand the structure of the tyrosine kinase domain of ROR1 and the newly discovered nontyrosine kinase functioning of ROR2 are required to explore possible targeting strategies.