The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2Hi macrophages in breast cancer and pancreatic neuroendocrine tumors

Allison S. Harney, George S. Karagiannis, Jeanine Pignatelli, Bryan D. Smith, Ece Kadioglu, Scott C. Wise, Molly M. Hood, Michael D. Kaufman, Cynthia B. Leary, Wei Ping Lu, Gada Al-Ani, Xiaoming Chen, David Entenberg, Maja H. Oktay, Yarong Wang, Lawrence Chun, Michele De Palma, Joan G. Jones, Daniel L. Flynn, John S. Condeelis

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Tumor-infiltrating myeloid cells promote tumor progression by mediating angiogenesis, tumor cell intravasation, and metastasis, which can offset the effects of chemotherapy, radiation, and antiangiogenic therapy. Here, we show that the kinase switch control inhibitor rebastinib inhibits Tie2, a tyrosine kinase receptor expressed on endothelial cells and protumoral Tie2-expressing macrophages in mouse models of metastatic cancer. Rebastinib reduces tumor growth and metastasis in an orthotopic mouse model of metastatic mammary carcinoma through reduction of Tie2+ myeloid cell infiltration, antiangiogenic effects, and blockade of tumor cell intravasation mediated by perivascular Tie2Hi/Vegf-AHi macrophages in the tumor microenvironment of metastasis (TMEM). The antitumor effects of rebastinib enhance the efficacy of microtubule inhibiting chemotherapeutic agents, either eribulin or paclitaxel, by reducing tumor volume, metastasis, and improving overall survival. Rebastinib inhibition of angiopoietin/Tie2 signaling impairs multiple pathways in tumor progression mediated by protumoral Tie2+ macrophages, including TMEM-dependent dissemination and angiopoietin/Tie2-dependent angiogenesis. Rebastinib is a promising therapy for achieving Tie2 inhibition in cancer patients.

Original languageEnglish (US)
Pages (from-to)2486-2501
Number of pages16
JournalMolecular cancer therapeutics
Volume16
Issue number11
DOIs
StatePublished - Nov 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Harney, A. S., Karagiannis, G. S., Pignatelli, J., Smith, B. D., Kadioglu, E., Wise, S. C., Hood, M. M., Kaufman, M. D., Leary, C. B., Lu, W. P., Al-Ani, G., Chen, X., Entenberg, D., Oktay, M. H., Wang, Y., Chun, L., De Palma, M., Jones, J. G., Flynn, D. L., & Condeelis, J. S. (2017). The selective Tie2 inhibitor rebastinib blocks recruitment and function of Tie2Hi macrophages in breast cancer and pancreatic neuroendocrine tumors. Molecular cancer therapeutics, 16(11), 2486-2501. https://doi.org/10.1158/1535-7163.MCT-17-0241