Introduction: Breast cancer is the most common cancer in women and is still the leading cause of cancer-related death in women in several countries. Chemotherapy combined with tumor removal surgery is the main treatment for breast cancer patients, but repeated resistance to chemotherapy drugs is an important factor in breast cancer recurrence and metastasis. The high extratumoral and intratumoral heterogeneity caused by genetic factors and the presence of cancer stem cells (CSCs) leads to the creation of cell populations with different sensitivity to treatment. CSCs are cancer cells with the characteristics of stem cells with the ability to self-renew. Differentiation and production of new tumors are defined and contribute to the development of tumor malignancies such as recurrence, metastasis, and multi-drug resistance. Breast cancer stem cells (BCSC) are a small part of breast cancer cells and have a high capacity to form tumors. Many intracellular signaling pathways such as WNT are critical regulators of BCSCs. WNT/ROR signaling is associated with tumor progression processes, such as cell proliferation, survival, invasion, or treatment resistance. Receptor tyrosine kinase ROR1 is a single transmembrane type I membrane protein, consisting of an extracellular part, a transmembrane part, and a cytoplasmic region. The extracellular part has an immunoglobulin-like domain (IG), cysteine-rich domain (CRD), and Kringle domain (KD). CRD modulates non-canonical WNT signaling by binding to the Wnt5a ligand. The cytoplasmic part is responsible for the activation of migration and cell proliferation signals and the serine/threonine-rich domain leads to resistance to apoptosis. In mature human tissues, ROR1 is expressed only at very low levels in areas such as the testis, parathyroid, and primary fibroblasts. As an encophthalic antigen, ROR1 is expressed physiologically in embryonic tissues and abnormally in hematological and solid cancers. IHC analysis has shown widespread expression of ROR1 in many tumors with significantly higher expression levels in cancerous tissue, especially breast cancer, than in adjacent normal tissue. Gene expression data show high levels, especially in poorly differentiated and triple-negative breast cancers. In the most aggressive subtype of breast cancer, the expression is very high (10%). Most studies have identified ROR1 as an oncogene. This finding stimulated the interest of cancer biologists to evaluate the potential of these new receptors as cancer biomarkers and their functional role in tumor development and progression. Besides the well-established function of RORs in cell proliferation, another deleterious consequence of active WNT/ROR signaling in cancer is the generation of tumor-resistant cell clones. reported upregulation of ROR1 or ROR2 in chemotherapy-resistant cancer cell lines. Studies show that ROR1 is associated with treatment-resistant cancer stem cells. Sabin and colleagues found that high expression of ROR promotes the reprogramming of somatic cells into induced pluripotent stem (iPS) cells. Zhang and colleagues found that ROR inhibits the expression of the cell proliferation inhibitory factor p53 by interacting with the heterogeneous RNA-binding protein nuclear ribonucleoprotein I, thereby promoting breast cancer proliferation. ROR1 is an excellent target for the development of therapeutic drugs for the treatment of breast cancer.
Methods: Several therapeutic strategies against ROR1 have been developed in clinical and preclinical trials. Several companies are developing anticancer therapies targeting ROR1, including monoclonal antibodies, antibody-drug conjugates (ADCs), dual antibodies, and CAR-T therapies. Among them, ADCs have faster development and good application prospects. ADCs consist of monoclonal antibodies conjugated to highly cytotoxic small molecules through chemical bonds. This coupling of the specificity of biological macromolecules and the cytotoxicity of small chemical drugs mediated by stable linkages has led to tremendous clinical success for ADCs.
Results: Among ROR1-based ADC drugs, Zilovertamab vedotin (MK2104, VLS-101) in phase Ⅱ and Ⅲ clinical trial, NBE-002 in phase Ⅱ, LCB-71 (CS5001) in phase Ⅰ, huXBR1-402-G5-PNU and huXBR1- 402-G5-PNU and cirmtuzumab-ADC-7 and ELN-11 are in pre-trial phase.
Conclusion: Considering the key role of ROR1 in the carcinogenic mechanisms of cancer cells, more efforts are needed to develop new drugs and improve existing drugs based on this compound.
Keywords: Antibody Drug Conjugate, Breast Cancer, Ror1, immunotherapy