Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 4; pp. 1370 - 1377
• Main Authors: Zhang, Suping, Zhang, Han, Ghia, Emanuela M., Huang, Jiajia, Wu, Liufeng, Zhang, Jianchao, Lam, Sharon, Lei, Yang, He, Jinsong, Cui, Bing, Widhopf, George F., Yu, Jian, Schwab, Richard, Messer, Karen, Jiang, Wenqi, Parker, Barbara A., Carson, Dennis A., Kipps, Thomas J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.01.2019
• Series: PNAS Plus
• Subjects: Adenosine Triphosphatases - metabolism; Animals; Antibodies, Monoclonal; Antineoplastic Agents - pharmacology; B-cell lymphoma; Bearing; Biological Sciences; Breast - drug effects; Breast - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer; Cell Line, Tumor; Cell self-renewal; Chemotherapy; Drug Resistance, Neoplasm - drug effects; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genes; Guanine nucleotide-binding protein; Heterografts; Homology; Humans; Immunoglobulins; Lymphoma; Metastases; Mice; Monoclonal antibodies; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; NIH 3T3 Cells; Nuclear Proteins - metabolism; Paclitaxel; Paclitaxel - pharmacology; Patients; PNAS Plus; Polycomb Repressive Complex 1 - metabolism; Protein-Serine-Threonine Kinases - metabolism; RAG2 protein; Receptor Tyrosine Kinase-like Orphan Receptors - metabolism; Spheroids; Stem cell transplantation; Stem cells; Transcription activation; Transcription Factors - metabolism; Tumors; Tyrosine; Xenografts; Xenotransplantation; Yes-associated protein; ROR1-signaling; cirmtuzumab; ROR1; chemotherapy; breast-cancer stem cells
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1816262116

Breast cancers enduring treatment with chemotherapy may be enriched for cancer stem cells or tumor-initiating cells, which have an enhanced capacity for self-renewal, tumor initiation, and/or metastasis. Breast cancer cells that express the type I tyrosine kinaselike orphan receptor ROR1 also may have such features. Here we find that the expression of ROR1 increased in breast cancer cells following treatment with chemotherapy, which also enhanced expression of genes induced by the activation of Rho-GTPases, Hippo-YAP/TAZ, or B lymphoma Mo-MLV insertion region 1 homolog (BMI1). Expression of ROR1 also enhanced the capacity of breast cancer cells to invade Matrigel, form spheroids, engraft in Rag2 − / − γ c − / − mice, or survive treatment with paclitaxel. Treatment of mice bearing breast cancer patient-derived xenografts (PDXs) with the humanized anti-ROR1 monoclonal antibody cirmtuzumab repressed expression of genes associated with breast cancer stemness, reduced activation of Rho-GTPases, Hippo-YAP/TAZ, or BMI1, and impaired the capacity of breast cancer PDXs to metastasize or reengraft Rag2 − / − γ c − / − mice. Finally, treatment of PDX-bearing mice with cirmtuzumab and paclitaxel was more effective than treatment with either alone in eradicating breast cancer PDXs. These results indicate that targeting ROR1 may improve the response to chemotherapy of patients with breast cancer.