Abstract
Abstract Tumor-associated macrophages (TAMs) and other tumor-infiltrating myeloid-derived cells are known to support tumor growth, proliferation and metastasis. Increased numbers of TAMs are also associated with poor prognosis in many solid tumors, including breast cancer. Previous studies have shown that targeting TAMs, either by re-programming or depletion, is an effective method to reduce solid tumor growth. MER, a receptor tyrosine kinase, is expressed on macrophages. MER-dependent signaling upon recognition and ingestion of apoptotic material (efferocytosis) suppresses proinflammatory cytokine production and increases secretion of immunosuppressive, wound healing cytokines. Recently we have identified MER as a potential therapeutic target in the tumor microenvironment utilizing polyoma middle T (PyVmT) orthotopic and transgenic models of breast cancer in Mertk-/- mice. Genetic deletion of MER in the tumor microenvironment led to a reduction in tumor growth, as well as increased proinflammatory cytokines and decreased IL-10 production. To further investigate the utility of MER inhibition in the tumor microenvironment as a therapeutic strategy, the efficacy of a first in class MER-selective, orally bioavailable, small molecule tyrosine kinase inhibitor (UNC TKI) was evaluated in immunocompetent C57Bl/6 mice implanted orthotopically with PyVmT mammary gland tumor cells. These PyVmT tumors cells do not express MER, AXL or TYRO3. Treatment with UNC TKI inhibited phosphorylation of MER in mouse macrophages in vitro, but did not affect survival of macrophages or MER-negative PyVmT tumor cells. However, after four weeks of daily treatment with UNC TKI, primary tumor growth was reduced two-fold compared to vehicle-treated tumor bearing mice. Serum IL-10 and IL-4 levels were reduced by 20% and 30%, respectively, in UNC TKI treated tumor-bearing mice compared to vehicle-treated tumor-bearing mice. Taken together, these data suggest that MER inhibition in the tumor microenvironment reduces tumor growth by altering the immunosuppressive environment and stimulating anti-tumor immunity. Moreover, these data validate UNC TKI as a promising strategy for immune-mediated treatment of breast cancer. Citation Format: Kristen M. Jacobsen, Deborah DeRyckere, Weihe Zhang, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Douglas K. Graham. Targeted inhibition of MER tyrosine kinase in the tumor microenvironment decreases tumor growth in a mouse model of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3637. doi:10.1158/1538-7445.AM2014-3637
Published Version
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