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Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1370-1377. doi: 10.1073/pnas.1816262116. Epub 2019 Jan 8.

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

Author information

1
Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Pharmacology, International Cancer Center, Shenzhen University Health Science Center, 518060 Shenzhen, China.
2
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093.
3
State Key Laboratory of Oncology in South China, Department of Medical Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060 Guangzhou, China.
4
Department of Breast Surgery, The Peking University Shenzhen Hospital, 518036 Shenzhen, China.
5
Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA 92093.
6
Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Pharmacology, International Cancer Center, Shenzhen University Health Science Center, 518060 Shenzhen, China; dcarson@ucsd.edu tkipps@ucsd.edu.

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.

KEYWORDS:

ROR1; ROR1-signaling; breast-cancer stem cells; chemotherapy; cirmtuzumab

PMID:
30622177
PMCID:
PMC6347692
DOI:
10.1073/pnas.1816262116
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: Cirmtuzumab was developed by T.J.K. in the T.J.K. laboratory and licensed by the University of California to Onternal Therapeutics, Inc., which provided stock options and research funding to the T.K.J. laboratory.

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