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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Animals
  • Antibodies, Monoclonal
  • Antineoplastic Agents / pharmacology*
  • Breast / drug effects
  • Breast / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / 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*
  • Neoplastic Stem Cells / 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

Substances

  • 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