ROR1 and ROR2 in Human Malignancies: Potentials for Targeted Therapy

Guilly Rebagay,Nai-Kong Cheung,Su Yan,Cheng Liu

doi:10.3389/fonc.2012.00034

Guilly Rebagay, Nai-Kong Cheung + Show 2 more

Open Access

https://doi.org/10.3389/fonc.2012.00034

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Abstract

Targeted therapies require cellular protein expression that meets specific requirements that will maximize effectiveness, minimize off-target toxicities, and provide an opportunity for a therapeutic effect. The receptor tyrosine kinase-like orphan receptors (ROR) are possible targets for therapy that may meet such requirements. RORs are transmembrane proteins that are part of the receptor tyrosine kinase (RTK) family. The RORs have been shown to play a role in tumor-like behavior, such as cell migration and cell invasiveness and are normally not expressed in normal adult tissue. As part of the large effort in target discovery, ROR proteins have recently been found to be expressed in human cancers. Their unique expression profiles may provide a novel class of therapeutic targets for small molecules against the kinase or for antibody-based therapies against these receptors. Being restricted on tumor cells and not on most normal tissues, RORs are excellent targets for the treatment of minimal residual disease, the final hurdle in the curative approach to many cancers, including solid tumors such as neuroblastoma. In this review, we summarize the biology of RORs as they relate to human cancer, and highlight the therapeutic approaches directed toward them.

Highlights

The receptor tyrosine kinase-like orphan receptors (ROR) are transmembrane proteins that are part of the receptor tyrosine kinase (RTK) family. They are related to the tropomyosin receptor kinase (Trk)–RTK, muscle-specific kinase (MuSK), and neurotrophic tyrosine kinase (NTRTK) receptor families (Masiakowski and Carroll, 1992; Forrester et al, 1999)
Homozygous mutations in ROR2 have been shown to be responsible for the Robinow syndrome, a skeletal dysplasia syndrome characterized by generalized limb shortening, segmental defects of the spine, and dysmorphic facial appearance, while heterozygous mutations have been found in patients with dominant brachydactyly B1, characterized by terminal deficiency of fingers and toes (Afzal et al, 2000; Afzal and Jeffery, 2003)
ROR1 is upregulated in B-cell chronic lymphocytic leukemia (B-CLL; Baskar et al, 2008), B-cell acute lymphocytic leukemia (B-acute lymphoblastic leukemia (ALL); Shabani et al, 2008), and mantle cell leukemia (MCL; Hudecek et al, 2010), while ROR2 is overexpressed in osteosarcoma (OS; Morioka et al, 2009), and renal cell carcinoma (RCC; Wright et al, 2009)

Summary

INTRODUCTION

The receptor tyrosine kinase-like orphan receptors (ROR) are transmembrane proteins that are part of the receptor tyrosine kinase (RTK) family. The ROR2/Wnt5a pathway has been shown to involve signaling through Wnt-c-Jun N-terminal kinase (Jnk) via activation of the actin binding protein, filamin A, which binds to the PRD intracellular domain in vertebrates (Oishi et al, 2003; Nomachi et al, 2008). Through activation of this pathway, mice fibroblasts could be induced to undergo cellular migration and invasion, features pathognomonic of malignancy. A similar finding was found in RCC cells, in which ROR2 regulated MMP2, shown to be overexpressed in many metastatic cancers (Kurban et al, 2006) and play a important role in the renal tubular cell epithelial to mesenchymal transformation during wound www.frontiersin.org healing, leading to ECM remodeling and subsequent invasive growth (Wright et al, 2009)

THERAPEUTIC APPROACH AGAINST ROR

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