The cytoplasmic localisation of ROR1 has not been adequately examined or understood to date.Ĭontradictory roles for ROR2 have been reported in various cancers. This was confirmed by Balakrishnan et al., who developed a monoclonal antibody with careful consideration to specifically address ambiguities in previous studies. However, numerous studies have consistently demonstrated cytoplasmic rather than cell surface expression of ROR1 by immunohistochemistry on both frozen and formalin-fixed, paraffin-embedded tumour samples. This is based on the bioinformatic prediction of the principal variant of ROR1 as a cell surface receptor as well as studies that have demonstrated cell surface expression of ROR1. The current understanding of the tumourigenic role and targeted therapeutic strategies for ROR1 is based on the premise that it is a cell surface receptor activated by Wnt5A. Since therapies inhibiting ROR1 have been shown to be well tolerated in Phase 1 clinical trials, ROR1 is now considered an elite member of the druggable genome (the subset of genes that can be pharmacologically regulated). Preclinical studies are also developing and evaluating additional therapeutic strategies targeting ROR1 in a growing list of cancers. Several therapeutic strategies targeting ROR1 have reached Phase I/II clinical trials, which include a monoclonal antibody (zilovertamab), antibody-drug conjugates (ADC NBE-002 and VLS-101), chimeric antigen receptor (CAR) T cell therapy and bispecific antibody (BiTE) to ROR1 and CD3 (NVG-111), for an array of malignancies. Since its identification in 1992, a pro-tumourigenic role for ROR1 signalling has been established in a growing list of both haematological malignancies (including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and acute lymphoblastic leukemia (ALL)), and solid tumours (including ovarian, endometrial, lung and chemotherapy-resistant breast cancer. The binding of Wnt5A (considered the primary ligand) to ROR1/2 activates non-canonical (β-catenin independent) Wnt signalling. Multiple studies have identified Wnt5A/B and Wnt16 as cognate ligands for the receptors hence they can no longer be considered orphans. Receptor tyrosine kinase-like orphan receptors 1 (ROR1) and ROR2 are members of the receptor tyrosine kinase family and are reported to be cell surface receptors comprising extracellular, transmembrane and intracellular domains. Studies exploring the function and significance of the predominantly expressed ROR1 transcript variant ENST00000545203 are warranted. ROR1/2 expression in healthy human tissues should be carefully considered for safety assessment of targeted therapy. ENST00000375708 is the predominantly expressed transcript variant of ROR2. Our analysis identifies predominant expression of ROR1 transcript variant ENST00000545203, which lacks a signal peptide for cell surface localisation, rather than the predicted principal variant ENST00000371079. ROR1/2 mRNA and transcript variant expression was detected in various non-diseased tissues. ROR1/2 have four and eight transcript variants, respectively. ROR1/2 transcript variant sequences, signal peptides for cell surface localisation, and mRNA and transcript variant expression were examined in 34 transcriptomic datasets including 33 cancer types and 54 non-diseased human tissues. Expression of ROR1/2 mRNA and transcript variants has not been systematically examined thus far. ROR1/2 are putative druggable targets increasing in significance in translational oncology.
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