Karvonen Hanna, Niininen Wilhelmiina, Murumägi Astrid, Ungureanu Daniela
BioMediTech, BMT, University of Tampere, Tampere 33014, Finland.
Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland.
Biochem Soc Trans. 2017 Apr 15;45(2):457-464. doi: 10.1042/BST20160272.
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the ROR receptor family consisting of two closely related type I transmembrane proteins ROR1 and ROR2. Owing to mutations in their canonical motifs required for proper kinase activity, RORs are classified as pseudokinases lacking detectable catalytic activity. ROR1 stands out for its selective and high expression in numerous blood and solid malignancies compared with a minimal expression in healthy adult tissues, suggesting high potential for this molecule as a drug target for cancer therapy. Current understanding attributes a survival role for ROR1 in cancer cells; however, its oncogenic function is cancer-type-specific and involves various signaling pathways. High interest in ROR1-targeted therapies resulted in the development of ROR1 monoclonal antibodies such as cirmtuzumab, currently in a phase I clinical trial for chronic lymphocytic leukemia. Despite these advances in translational studies, the molecular mechanism employed by ROR1 in different cancers is not yet fully understood; therefore, more insights into the oncogenic role of ROR1 signaling are crucial in order to optimize the use of targeted drugs. Recent studies provided evidence that targeting ROR1 simultaneously with inhibition of B-cell receptor (BCR) signaling is more effective in killing ROR1-positive leukemia cells, suggesting a synergistic correlation between co-targeting ROR1 and BCR pathways. Although this synergy has been previously reported for B-cell acute lymphoblastic leukemia, the molecular mechanism appears rather different. These results provide more insights into ROR1-BCR combinatorial treatment strategies in hematological malignancies, which could benefit in tailoring more effective targeted therapies in other ROR1-positive cancers.
受体酪氨酸激酶样孤儿受体1（ROR1）是ROR受体家族的成员，该家族由两个密切相关的I型跨膜蛋白ROR1和ROR2组成。由于其正常激酶活性所需的典型基序发生突变，ROR被归类为缺乏可检测催化活性的假激酶。与健康成人组织中极低的表达相比，ROR1在众多血液和实体恶性肿瘤中具有选择性的高表达，这表明该分子作为癌症治疗药物靶点具有很高的潜力。目前的认识认为ROR1在癌细胞中具有生存作用；然而，其致癌功能具有癌症类型特异性，涉及多种信号通路。对ROR1靶向治疗的高度关注导致了ROR1单克隆抗体的开发，如cirmtuzumab，目前正在进行慢性淋巴细胞白血病的I期临床试验。尽管在转化研究方面取得了这些进展，但ROR1在不同癌症中所采用的分子机制尚未完全了解；因此，更深入了解ROR1信号传导的致癌作用对于优化靶向药物的使用至关重要。最近的研究提供了证据，表明同时靶向ROR1和抑制B细胞受体（BCR）信号传导在杀死ROR1阳性白血病细胞方面更有效，这表明共同靶向ROR1和BCR途径之间存在协同相关性。尽管此前已报道B细胞急性淋巴细胞白血病存在这种协同作用，但其分子机制似乎有很大不同。这些结果为血液系统恶性肿瘤中ROR1-BCR联合治疗策略提供了更多见解，这可能有助于为其他ROR1阳性癌症量身定制更有效的靶向治疗。
