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

Abstract

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-/-[Formula: see text] 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-/-[Formula: see text] 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.

• Authors: Suping Zhang, Han Zhang, Emanuela M Ghia, Jiajia Huang, Liufeng Wu, Jianchao Zhang, Sharon Lam, Yang Lei, Jinsong He, Bing Cui, George F Widhopf 2nd, Jian Yu, Richard Schwab, Karen Messer, Wenqi Jiang, Barbara A Parker, Dennis A Carson, Thomas J Kipps
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 4 Pg. 1370-1377 (01 22 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 30622177 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 the Author(s). Published by PNAS.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Nuclear Proteins
• Transcription Factors
• Polycomb Repressive Complex 1
• ROR1 protein, human
• Receptor Tyrosine Kinase-like Orphan Receptors
• Protein Serine-Threonine Kinases
• Adenosine Triphosphatases
• rho-ATPase
• Paclitaxel

Topics

• Adenosine Triphosphatases (metabolism)
• Animals
• Antibodies, Monoclonal
• Antineoplastic Agents (pharmacology)
• Breast (drug effects, metabolism)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterografts
• Humans
• Mice
• NIH 3T3 Cells
• Neoplastic Stem Cells (drug effects, metabolism)
• Nuclear Proteins (metabolism)
• Paclitaxel (pharmacology)
• Polycomb Repressive Complex 1 (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Receptor Tyrosine Kinase-like Orphan Receptors (metabolism)
• Transcription Factors (metabolism)