Abstract
The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.
Highlights
Since the discovery of the INT1 proto-oncogene, known as WNT1, and its identification as a key mediator of tumorigenesis, WNT signaling has evolved as one of the main pathways implicated in cancer development and progression
Similar results were obtained from an IHC study in which 57% of triple-negative breast cancers stained highly positive for ROR1, whereas signals were detected in only 12% of the estrogen receptor (ER)
While most reports did not find any indications of an interaction of ROR1 with canonical WNT ligands or with the induction of a β-catenindependent signaling in cancer cells [33,56,105], many reports described an inhibitory function of ROR2 on β-catenin-dependent WNT signaling [2,24,125,131,155]
Summary
Since the discovery of the INT1 proto-oncogene, known as WNT1, and its identification as a key mediator of tumorigenesis, WNT signaling has evolved as one of the main pathways implicated in cancer development and progression. It can be activated by the binding of canonical WNT ligands (e.g., WNT3A) to a FZD receptor and the co-receptor low-density lipoprotein receptor-related protein 5/6 (LRP5/6). DSH inhibits the destruction complex, consisting of adenomatous polyposis coli protein (APC), AXIN, Casein kinase 1 (CK-1), and glycogen synthase kinase-3 (GSK-3), which usually constitutively targets β-catenin for degradation This inhibition enables the translocation of β-catenin into the nucleus where it activates the transcription of target genes predominantly involved in the regulation of cell fate, proliferation, and differentiation [3]. It has become apparent that at least one other subpathway exists in addition to the two established non-canonical WNT subpathways, namely WNT/ROR signaling via the two receptor tyrosine kinase-like orphan receptors (RORs), ROR1 and ROR2 Both belong to the receptor tyrosine kinase (RTK) family, and they had initially been described as orphan receptors, WNT proteins have been identified as their long-missing ligands. We will give a comprehensive overview about the downstream signaling elicited by ROR1 and ROR2, and revisit the current treatment strategies and first promising clinical data for targeting the WNT/ROR pathway in the context of cancer
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