Targeting the "Hidden Target" ROR1: A Breakthrough for Broad-Spectrum Cancer Therapy?

2. ROR1-Related Signaling Pathways

The activation of ROR1 signaling relies on ligand binding, which subsequently regulates tumor biology through downstream pathways. The main pathways include:

2.1 Wnt5a-ROR1 Pathway

Wnt5a is the canonical ligand of ROR1. Their binding activates the non-canonical Wnt signaling pathway:

Figure 2. ROR1 signaling ^[1]

• Activation of the NF-κB pathway: Promotes the accumulation of p62, inhibits KEAP1-mediated degradation of NRF2, upregulates antioxidant genes, and enhances drug resistance in tumor cells ^[1].
• Activation of the PI3K/AKT/mTOR pathway: AKT phosphorylation promotes cell survival and proliferation ^[1].
• Activation of ERK1/2 and Rho/Rac GTPases: Activation of the Ras-MAPK pathway through molecules such as DOCK2 and Grb2, enhancing cell migration and invasion ^[1].

2.2 IGFBP5-ROR1/HER2 Pathway

In glioblastoma, insulin-like growth factor-binding protein 5 (IGFBP5) acts as a novel ligand for ROR1. Binding of IGFBP5 to ROR1 promotes the formation of a heterodimer with HER2, activating the CREB transcription factor, upregulating the expression of ETV5 and FBXW9, and ultimately enhancing the invasiveness and tumorigenicity of cancer stem cells ^[8].

2.3 ROR1-STAT3 Pathway

In ovarian cancer, ROR1 indirectly promotes STAT3 phosphorylation through the AKT/ERK pathway. ROR1 and STAT3 are co-expressed in tumor stromal cells (e.g., cancer-associated fibroblasts), participating in the maintenance of tumor heterogeneity through inflammatory responses and transcriptional regulation ^[9].

2.4 Cross-Talk with Other Pathways

• With the BTK pathway: In mantle cell lymphoma, ROR1 activation is independent of the BCR/BTK pathway. Combination with BTK inhibitors can enhance anti-tumor effects ^[10].
• With the BCL2 pathway: In chronic lymphocytic leukemia (CLL), ROR1 upregulates BCL2L1 (encoding BCL-XL), reducing sensitivity to Venetoclax. Anti-ROR1 antibodies can reverse this drug resistance ^[6].

3. ROR1-Related Diseases

Aberrant expression of ROR1 is associated with various malignant tumors, including hematological malignancies and solid tumors:

3.1 Hematological Malignancies

3.1.1 Chronic Lymphocytic Leukemia (CLL)

ROR1 is specifically highly expressed in CLL, with over 90% of patients' leukemia cells detectable for ROR1 protein. Its expression level is closely related to disease progression ^[1,6]. ROR1 activates multiple signaling pathways through binding with its ligand Wnt5a:

• Anti-apoptotic pathway: Activation of NF-κB and upregulation of BCL2L1 (encoding BCL-XL) directly lead to resistance to BCL2 inhibitors such as Venetoclax ^[6].
• Proliferation and survival: Enhancing cell survival signals through the PI3K/AKT/mTOR pathway and promoting cell proliferation through ERK1/2 activation ^[1].
• Microenvironment interaction: Wnt5a-ROR1 signaling induces CLL cells to secrete cytokines such as IL-6, forming a pro-cancerous cycle through autocrine STAT3 activation^[1].

Clinical studies have shown that CLL patients with high ROR1 expression have significantly shorter treatment-free survival (TFS) and reduced sensitivity to BTK inhibitors like Ibrutinib.

3.1.2 Mantle Cell Lymphoma (MCL)

MCL cells universally overexpress ROR1, which has a cross-regulatory but independent relationship with the B cell receptor (BCR)-BTK pathway[10]. This includes:

• Drug resistance mechanism: ROR1 promotes cell proliferation through the activation of Rac1 and ERK1/2 pathways, which is independent of BCR signaling and is an important cause of BTK inhibitor resistance ^[10].
• Synergistic targeting effect: In TP53-mutated MCL models, combination of ROR1 monoclonal antibody (zilovertamab) with BTK inhibitors significantly enhances cytotoxicity by dual-blocking the NF-κB and MAPK pathways to induce apoptosis ^[10].

3.1.3 Non-Hodgkin Lymphoma

ROR1 transcripts are highly expressed in subtypes such as diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), making it a potential therapeutic target ^[4].

• DLBCL and FL: In situ hybridization (ISH) shows that the positivity rate of ROR1 transcripts in patients with DLBCL and FL reaches 60% and 55%, respectively. ROR1-targeted T cell engagers (TCE) can specifically activate T cells to kill tumor cells ^[4].
• Richter syndrome: In DLBCL transformed from CLL, high ROR1 expression activates the PI3K/AKT pathway, enhancing tumor invasiveness. Antibody-drug conjugates (ADCs) such as VLS-101 can specifically deliver toxins to ROR1+ cells ^[1].

3.2 Solid Tumors

3.2.1 Glioblastoma (GBM)

ROR1 expression in GBM is positively correlated with tumor grading. The mRNA level of ROR1 in high-grade GBM patients is 3.2 times that of low-grade gliomas ^[5,7]. Key mechanisms include:

• Invasion and metastasis: IGFBP5, as a novel ligand of ROR1, binds to ROR1 to promote the formation of a heterodimer with HER2, activating the CREB transcription factor, upregulating ETV5 and FBXW9 to enhance the invasiveness of cancer stem cells ^[8].
• Prognostic association: The median survival of GBM patients with high ROR1 expression is only 16 months, significantly lower than that of low expressers (70 months), and is associated with increased tumor recurrence ^[7].

3.2.2 Lung Cancer, Breast Cancer, and Liver Cancer

ROR1 is highly expressed in these tumors. Humanized anti-ROR1 antibodies (h1B8, h6D4) can inhibit tumor growth ^[8].

• Lung cancer: In lung adenocarcinoma, ROR1 activates the PI3K/AKT pathway to promote cell proliferation. Anti-ROR1 humanized antibodies h1B8 and h6D4 can inhibit tumor growth by blocking this pathway ^[11].
• Breast cancer: In triple-negative breast cancer (TNBC), ROR1 co-expresses with EGFR, enhancing metastatic ability through ERK1/2 activation. The h6D4 antibody can significantly reduce the formation of pulmonary metastases ^[11].
• Liver cancer: In hepatocellular carcinoma (HCC), ROR1 activates the β-catenin pathway in a Wnt5a-dependent manner. The h1B8 antibody can downregulate cyclin D1 expression to inhibit cell cycle progression ^[11].

3.2.3 Ovarian Cancer

In high-grade serous ovarian cancer (HGSOC), ROR1 expression significantly increases after neoadjuvant chemotherapy (NACT), which is associated with enhanced tumor heterogeneity. ROR1 is highly expressed in cancer-associated fibroblasts (CAFs), activating STAT3 through AKT/ERK, promoting the secretion of IL-6 and TGF-β to form a pro-metastatic microenvironment. ROR1+ CAFs secrete Wnt5b to promote epithelial-mesenchymal transition (EMT), reducing platinum drug sensitivity ^[9].

3.2.4 Gynecological Cancers

In gynecological tumors such as cervical cancer and endometrial cancer, the high expression rate of ROR1 reaches 45%-60%. Mechanistic studies have shown that ROR1 activates the Wnt5a/PI3K pathway to upregulate cyclin E1, accelerating the cell cycle process. ROR1 co-localizes with integrin β1, enhancing the adhesion of tumor cells to the extracellular matrix and promoting local infiltration ^[4].

3.3 Other Malignant Tumors

3.3.1 Pancreatic Cancer

In pancreatic ductal adenocarcinoma (PDAC), ROR1 is specifically highly expressed in cancer stem cells, maintaining stem cell characteristics through the activation of the Notch pathway ^[2]. The small molecule inhibitor KAN0439834 targets the ROR1 tyrosine kinase domain, inhibits downstream AKT phosphorylation, and reduces tumor volume by 58% in patient-derived xenograft (PDX) models ^[2].

3.3.2 Melanoma

ROR1 activates the RhoA/ROCK signal through the non-canonical Wnt pathway, enhancing cell migration ability. Clinical samples have shown that melanoma patients with high ROR1 expression have a distant metastasis rate 2.3 times that of low expressers and are associated with BRAF inhibitor resistance ^[1].

4. Latest Research Progress on ROR1-Targeted Drugs

Currently, there are several drug pipelines targeting ROR1 under development, mainly including ADCs, autologous CAR-T cells, and monoclonal antibodies. The indications cover hematological malignancies and solid tumors (such as lung cancer, breast cancer, lymphoma, etc.), with several drugs entering the late-stage clinical validation phase. This highlights the great potential of ROR1 as a broad-spectrum tumor target. Some of the ongoing pipelines are listed below:

5. CUSABIO ROR1-Related Product Recommendations

● ROR1 Recombinant Protein

Recombinant Human Inactive tyrosine-protein kinase transmembrane receptor ROR1 (ROR1), partial (Active); CSB-MP020067HU1d7

Recombinant Mouse Inactive tyrosine-protein kinase transmembrane receptor ROR1 (Ror1), partial (Active); CSB-MP4008MO

● ROR1 Antibodies

ROR1 Recombinant Monoclonal Antibody; CSB-RA020067A1HU

● ROR1 Stable Cell Lines

CT26/Human ROR1 Stable Cell Line; CSB-SC020067HU

HEK293T/Human ROR1 Stable Cell Line; CSB-SC020067HU2-E

MDA-MB-231/Human ROR1 Stable Cell Line; CSB-SC020067HU3-E

MC38/Human ROR1 Stable Cell Line; CSB-SC020067HU4-E