ROR1

Official Full Name

receptor tyrosine kinase like orphan receptor 1

Organism

Homo sapiens

GeneID

4919

Background

This gene encodes a receptor tyrosine kinase-like orphan receptor that modulates neurite growth in the central nervous system. The encoded protein is a glycosylated type I membrane protein that belongs to the ROR subfamily of cell surface receptors. It is a pseudokinase that lacks catalytic activity and may interact with the non-canonical Wnt signalling pathway. This gene is highly expressed during early embryonic development but expressed at very low levels in adult tissues. Increased expression of this gene is associated with B-cell chronic lymphocytic leukaemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2012]

Synonyms

NTRKR1; dJ537F10.1;

Bio Chemical Class

Kinase

Protein Sequence

MHRPRRRGTRPPLLALLAALLLAARGAAAQETELSVSAELVPTSSWNISSELNKDSYLTLDEPMNNITTSLGQTAELHCKVSGNPPPTIRWFKNDAPVVQEPRRLSFRSTIYGSRLRIRNLDTTDTGYFQCVATNGKEVVSSTGVLFVKFGPPPTASPGYSDEYEEDGFCQPYRGIACARFIGNRTVYMESLHMQGEIENQITAAFTMIGTSSHLSDKCSQFAIPSLCHYAFPYCDETSSVPKPRDLCRDECEILENVLCQTEYIFARSNPMILMRLKLPNCEDLPQPESPEAANCIRIGIPMADPINKNHKCYNSTGVDYRGTVSVTKSGRQCQPWNSQYPHTHTFTALRFPELNGGHSYCRNPGNQKEAPWCFTLDENFKSDLCDIPACDSKDSKEKNKMEILYILVPSVAIPLAIALLFFFICVCRNNQKSSSAPVQRQPKHVRGQNVEMSMLNAYKPKSKAKELPLSAVRFMEELGECAFGKIYKGHLYLPGMDHAQLVAIKTLKDYNNPQQWTEFQQEASLMAELHHPNIVCLLGAVTQEQPVCMLFEYINQGDLHEFLIMRSPHSDVGCSSDEDGTVKSSLDHGDFLHIAIQIAAGMEYLSSHFFVHKDLAARNILIGEQLHVKISDLGLSREIYSADYYRVQSKSLLPIRWMPPEAIMYGKFSSDSDIWSFGVVLWEIFSFGLQPYYGFSNQEVIEMVRKRQLLPCSEDCPPRMYSLMTECWNEIPSRRPRFKDIHVRLRSWEGLSSHTSSTTPSGGNATTQTTSLSASPVSNLSNPRYPNYMFPSQGITPQGQIAGFIGPPIPQNQRFIPINGYPIPPGYAAFPAAHYQPTGPPRVIQHCPPPKSRSPSSASGSTSTGHVTSLPSSGSNQEANIPLLPHMSIPNHPGGMGITVFGNKSQKPYKIDSKQASLLGDANIHGHTESMISAEL

Open

Disease

Diffuse large B-cell lymphoma, Leukaemia, Mature B-cell leukaemia, Mature B-cell lymphoma, Prostate cancer, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

7 +

Discontinued Drug

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Detailed Information

The ROR1 gene, located on human chromosome 1p31.3, encodes a type I transmembrane protein that belongs to the ROR receptor family. This protein consists of 937 amino acids, with an extracellular region containing an immunoglobulin-like domain, a cysteine-rich Frizzled-like (FZD) domain, and a near-membrane Kringle domain, while the intracellular region exhibits features of a pseudokinase domain. Structural studies indicate that the FZD domain mediates binding to the Wnt5a ligand, whereas the Kringle domain participates in recognizing macromolecular structures and facilitating signal complex assembly. Despite the presence of a kinase-like domain, ROR1 exhibits negligible catalytic activity in vivo, functioning primarily through protein-protein interactions and classifying it as a typical pseudokinase.

Signaling Pathways

ROR1 mediates signaling primarily through interaction with WNT proteins, such as WNT5a, activating downstream pathways including MAPK/ERK, STAT3, and NF-κB, which regulate cell proliferation, survival, epithelial-mesenchymal transition (EMT), and resistance to therapy. Additionally, ROR1 interacts with other pathways such as PI3K/AKT/mTOR, BMI-1, and YAP/TAZ, further modulating tumor cell behavior.

ROR1 Expression and Function in Hematologic Malignancies

In chronic lymphocytic leukemia (CLL), ROR1 has been recognized as a disease-specific marker since 2001, with expression levels increasing during disease progression. ROR1 expression correlates with poor prognosis and promotes tumor cell survival, proliferation, migration, and drug resistance by activating associated signaling pathways, inhibiting pro-apoptotic proteins, and enhancing anti-apoptotic proteins. ROR1 expression in CLL is linked to BCL2, with del(13q) causing loss of miRNA-15a and miRNA-16-1, resulting in overexpression of both ROR1 and BCL2. Although most CLL patients exhibit high ROR1 expression, approximately 5% show very low levels. High ROR1 expression is associated with shorter progression-free survival and overall survival, as well as resistance to venetoclax.

In mantle cell lymphoma (MCL), ROR1 is highly expressed and correlates with increased cell proliferation. ROR1 forms complexes with CD19 to promote MCL cell growth, while silencing ROR1 inhibits proliferation and increases cell death. MCL is a rare B-cell non-Hodgkin lymphoma characterized by chromosomal translocations, with treatment strategies including chemotherapy, immunotherapy, and targeted therapy.

In diffuse large B-cell lymphoma (DLBCL), ROR1 expression is associated with poor prognosis and is more frequently observed in primary refractory DLBCL, Richter’s syndrome, and transformed follicular lymphoma. Knockdown of ROR1 inhibits DLBCL cell growth. Despite standard treatments such as R-CHOP and rituximab, a subset of patients relapse or are refractory, highlighting the need for novel therapeutic targets.

In acute myeloid leukemia (AML), ROR1 is expressed in approximately 35% of patient cells and in AML cell lines, including THP1, MV4-11, and NB4, suggesting potential efficacy of ROR1-targeted therapies.

Figure 1. ROR1 signaling activates tumor growth through WNT-FZD interactions, while targeted therapies inhibit ROR1-mediated survival and proliferation. (Tigu AB, et al., 2024)

Therapeutic Strategies Targeting ROR1

Small molecule inhibitors such as KAN0441571C and KAN0439834 target extracellular or intracellular ROR1 domains, blocking its activity and downstream signaling, and have been shown to induce apoptosis in CLL, MCL, and DLBCL cells. Monoclonal antibodies, including cirmtuzumab (UC-961) and other anti-ROR1 mAbs, induce cytotoxicity and inhibit ROR1-mediated signaling. Cirmtuzumab has demonstrated efficacy in CLL and MCL patients, reducing tumor cell numbers, with potential synergistic effects when combined with venetoclax. Antibody-drug conjugates (ADCs) such as zilovertamab vedotin (ZV), huXBR1-402-G5-PNU, and CS5001 target ROR1-expressing tumor cells to deliver cytotoxic payloads, showing anti-tumor activity and manageable safety profiles in preclinical and early clinical studies. CAR-T cell and bispecific T-cell engager (BiTE) therapies genetically engineer T cells to target ROR1 or simultaneously engage CD3 and ROR1, demonstrating tumor cell lysis in CLL and MCL, although potential toxicity exists due to ROR1 expression in normal tissues.

Summary and Outlook

ROR1 is overexpressed in various hematologic malignancies, contributing to tumor development, progression, and drug resistance, and represents a promising therapeutic target. Multiple ROR1-directed strategies are in development or clinical trials, including small molecules, monoclonal antibodies, ADCs, CAR-T cells, and BiTEs, with some showing encouraging efficacy and safety. Future research will focus on further elucidating ROR1’s biological functions and signaling pathways, optimizing therapeutic strategies through combination therapies and novel agents, improving efficacy, overcoming resistance, and minimizing toxicity to provide more effective treatments for patients with hematologic malignancies.

Reference

Tigu AB, Munteanu R, Moldovan C, et al. Therapeutic advances in the targeting of ROR1 in hematological cancers. Cell Death Discov. 2024 Nov 17;10(1):471
Kipps TJ. ROR1: an orphan becomes apparent. Blood. 2022 Oct 6;140(14):1583-1591.
Osorio-Rodríguez DA, Camacho BA, Ramírez-Segura C. Anti-ROR1 CAR-T cells: Architecture and performance. Front Med (Lausanne). 2023 Feb 17;10:1121020.

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