Ror2 As a Therapeutic Target in Cancer

Overview

Journal Pharmacol Ther

Specialty Pharmacology

Date 2015 Jan 24

PMID 25614331

Citations 52

Authors

Zufan Debebe

W Kimryn Rathmell

Affiliations

Soon will be listed here.

Abstract

Ror2 is a signaling receptor for Wnt ligands that is known to play important roles in limb development, but having no essential roles known in adult tissues. Recent evidence has implicated Ror2 in mediating both canonical and non-canonical signaling pathways. Ror2 was initially found to be highly expressed in osteosarcoma and renal cell carcinomas, and has recently been found in an increasingly long list of cancers currently including melanoma, colon cancer, melanoma, squamous cell carcinoma of the head and neck, and breast cancer. In the majority of these cancer types, Ror2 expression is associated with more aggressive disease states, consistent with a role mediating Wnt signaling regardless of the canonical or noncanonical signal. Because of the pattern of tissue distribution, the association with high-risk diseases, and the cell surface localization of this receptor, Ror2 has been identified as a potential high value target for therapeutic development. However, the recent discovery that Ror2 may function through non-kinase activities challenges this strategy and opens up opportunities to target this important molecule through alternative means.

Citing Articles

Model ensembling as a tool to form interpretable multi-omic predictors of cancer pharmacosensitivity.

De Landtsheer S, Badkas A, Kulms D, Sauter T Brief Bioinform. 2024; 25(6).

PMID: 39494610 PMC: 11532660. DOI: 10.1093/bib/bbae567.

Unlocking the potential: advancements and future horizons in ROR1-targeted cancer therapies.

Li L, Huang W, Ren X, Wang Z, Ding K, Zhao L Sci China Life Sci. 2024; 67(12):2603-2616.

PMID: 39145866 DOI: 10.1007/s11427-024-2685-9.

miR-124-3p and miR-194-5p regulation of the PI3K/AKT pathway via ROR2 in medulloblastoma progression.

Wang C, Fu R, Wang Y, Wei J, Yu Y, Hu L Cancer Gene Ther. 2024; 31(6):941-954.

PMID: 38632356 PMC: 11192632. DOI: 10.1038/s41417-024-00762-y.

ROR2/Wnt5a Signaling Regulates Directional Cell Migration and Early Tumor Cell Invasion in Ovarian Cancer.

Grither W, Baker B, Morikis V, Ilagan M, Fuh K, Longmore G Mol Cancer Res. 2024; 22(5):495-507.

PMID: 38334461 PMC: 11065611. DOI: 10.1158/1541-7786.MCR-23-0616.

Analysis of the differentially expressed genes in the combs and testes of Qingyuan partridge roosters at different developmental stages.

Qi H, Deng Z, Ye F, Gou J, Huang M, Xiang H BMC Genomics. 2024; 25(1):33.

PMID: 38177997 PMC: 10768254. DOI: 10.1186/s12864-024-09960-2.

References

Kobayashi M, Shibuya Y, Takeuchi J, Murata M, Suzuki H, Yokoo S . Ror2 expression in squamous cell carcinoma and epithelial dysplasia of the oral cavity. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009; 107(3):398-406. DOI: 10.1016/j.tripleo.2008.08.018. View

Yamamoto H, Yoo S, Nishita M, Kikuchi A, Minami Y . Wnt5a modulates glycogen synthase kinase 3 to induce phosphorylation of receptor tyrosine kinase Ror2. Genes Cells. 2007; 12(11):1215-23. DOI: 10.1111/j.1365-2443.2007.01128.x. View

OConnell M, Fiori J, Xu M, Carter A, Frank B, Camilli T . The orphan tyrosine kinase receptor, ROR2, mediates Wnt5A signaling in metastatic melanoma. Oncogene. 2009; 29(1):34-44. PMC: 2803338. DOI: 10.1038/onc.2009.305. View

Hojjat-Farsangi M . Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci. 2014; 15(8):13768-801. PMC: 4159824. DOI: 10.3390/ijms150813768. View

Roman-Gomez J, Jimenez-Velasco A, Cordeu L, Vilas-Zornoza A, Jose-Eneriz E, Garate L . WNT5A, a putative tumour suppressor of lymphoid malignancies, is inactivated by aberrant methylation in acute lymphoblastic leukaemia. Eur J Cancer. 2007; 43(18):2736-46. DOI: 10.1016/j.ejca.2007.10.004. View

Forrester W . The Ror receptor tyrosine kinase family. Cell Mol Life Sci. 2002; 59(1):83-96. PMC: 11337485. DOI: 10.1007/s00018-002-8407-9. View

Akbarzadeh S, Wheldon L, Sweet S, Talma S, Mardakheh F, Heath J . The deleted in brachydactyly B domain of ROR2 is required for receptor activation by recruitment of Src. PLoS One. 2008; 3(3):e1873. PMC: 2268744. DOI: 10.1371/journal.pone.0001873. View

OConnell M, Weeraratna A . Hear the Wnt Ror: how melanoma cells adjust to changes in Wnt. Pigment Cell Melanoma Res. 2009; 22(6):724-39. PMC: 2766021. DOI: 10.1111/j.1755-148X.2009.00627.x. View

Forbes S, Bhamra G, Bamford S, Dawson E, Kok C, Clements J . The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc Hum Genet. 2008; Chapter 10:Unit 10.11. PMC: 2705836. DOI: 10.1002/0471142905.hg1011s57. View

10.

Oishi I, Sugiyama S, Liu Z, Yamamura H, Nishida Y, Minami Y . A novel Drosophila receptor tyrosine kinase expressed specifically in the nervous system. Unique structural features and implication in developmental signaling. J Biol Chem. 1997; 272(18):11916-23. DOI: 10.1074/jbc.272.18.11916. View

11.

Matsuda T, Nomi M, Ikeya M, Kani S, Oishi I, Terashima T . Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development. Mech Dev. 2001; 105(1-2):153-6. DOI: 10.1016/s0925-4773(01)00383-5. View

12.

Manning G, Whyte D, Martinez R, Hunter T, Sudarsanam S . The protein kinase complement of the human genome. Science. 2002; 298(5600):1912-34. DOI: 10.1126/science.1075762. View

13.

Wouda R, Bansraj M, de Jong A, Noordermeer J, Fradkin L . Src family kinases are required for WNT5 signaling through the Derailed/RYK receptor in the Drosophila embryonic central nervous system. Development. 2008; 135(13):2277-87. DOI: 10.1242/dev.017319. View

14.

Lee S, Lim S, Kang S, Suh S, Suh Y . Prognostic significance of Ror2 and Wnt5a expression in medulloblastoma. Brain Pathol. 2013; 23(4):445-53. PMC: 8029459. DOI: 10.1111/bpa.12017. View

15.

Petrova I, Lahaye L, Martianez T, de Jong A, Malessy M, Verhaagen J . Homodimerization of the Wnt receptor DERAILED recruits the Src family kinase SRC64B. Mol Cell Biol. 2013; 33(20):4116-27. PMC: 3811672. DOI: 10.1128/MCB.00169-13. View

16.

Shawver L, Slamon D, Ullrich A . Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell. 2002; 1(2):117-23. DOI: 10.1016/s1535-6108(02)00039-9. View

17.

Huang D, Jiang S, Zhang Y, Liu X, Zhang J, He R . A new mutation in the gene ROR2 causes brachydactyly type B1. Gene. 2014; 547(1):106-10. DOI: 10.1016/j.gene.2014.06.035. View

18.

Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T . Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med. 2012; 18(3):405-12. DOI: 10.1038/nm.2653. View

19.

Nishita M, Yoo S, Nomachi A, Kani S, Sougawa N, Ohta Y . Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. J Cell Biol. 2006; 175(4):555-62. PMC: 2064592. DOI: 10.1083/jcb.200607127. View

20.

Da Forno P, Pringle J, Hutchinson P, Osborn J, Huang Q, Potter L . WNT5A expression increases during melanoma progression and correlates with outcome. Clin Cancer Res. 2008; 14(18):5825-32. DOI: 10.1158/1078-0432.CCR-07-5104. View