Abstract #1789: Cellular activity of ABT-869 against colony-stimulating-factor-1 receptor (CSF-1R) in macrophage-like cell lines

ABT-869 is a potent inhibitor of the VEGFR and PDGFR families of receptor tyrosine kinases, including c-fms (CSF-1R). Colony-stimulating-factor-1 (CSF-1) signaling through CSF-1R is elevated in several diseases including many types of carcinoma. Most tumors contain an appreciable infiltrate of tumor associated macrophages (TAMs) that are polarized to the M2 phenotype associated with angiogenesis. CSF-1 (M-CSF) is a potent chemoattractant for macrophages and recruits macrophages into tumor tissues where they adopt this tumor promoting phenotype. Ablation of macrophages or neutralization of CSF-1 attenuates tumor growth and increases chemosenstivity of some tumors in vivo. Herein, we evaluated the selectivity of ABT-869 and four other small molecule VEGFR/PDGFR family inhibitors against CSF-1 signaling in various macrophage-like cell lines. ABT-869 potently inhibits the catalytic activity of the CSF-1R kinase in vitro (IC 50 = 5 nM) and more importantly human CSF-1R signaling in transfected NIH 3T3 cells (IC 50 = 24 nM; Guo, J. et al. (2006) Mol. Cancer Ther. 5: 787); however, demonstration of activity against endogenous CSF-1R has not been reported. The murine myeloid cell line M-NSF-60 was chosen as a model system to evaluate the effect of ABT-869 on endogenous CSF-1R signaling as this cell line is dependent on CSF-1 or IL-3 for growth. ABT-869 was found to potently inhibit the CSF-1-dependent growth of M-NFS-60 and RAW 264.7 cells, with IC 50 values of 30 and 50 nM, respectively. In contrast, ABT-869 weakly inhibited the IL-3-dependent growth of M-NFS-60 cells (IC 50 = 4,400 nM) and the CSF-1-independent (10% FBS) growth of RAW 264.7 cells (IC 50 = 8,600 nM), demonstrating selectivity for CSF-1 signaling in these cell lines. The four reference compounds (sorafenib, sunitinib, cediranib and axitinib) demonstrated little or no separation of effects on CSF-1 and IL-3 dependent growth in M-NSF-60 cells. Inhibition of CSF-1R signaling in vivo was demonstrated in a CSF-1 primed model of LPS-induced TNF\#945; release in mice. At doses of 3 to 25 mg/kg, orally, ABT-869 reduced the CSF-1 primed release of TNF\#945; to non-primed levels. These results demonstrate that ABT-869 has potent activity against CSF-1R signaling both in vitro and in vivo, and suggests that ABT-869 may have value in treating cancers where elevated levels of inflammatory TAMs drive tumor progression. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1789.