CSF1R inhibitors exhibit anti-tumor activity in acute myeloid leukemia by blocking paracrine signals from support cells
Chen, Y., Lakshmikanth, T., Olin, A. et al.
To identify new therapeutic targets in AML, we performed small-molecule and siRNA screens of primary AML patient samples. In 23% of samples, we found sensitivity to inhibition of CSF1R, a receptor tyrosine kinase responsible for survival, proliferation, and differentiation of myeloid-lineage cells. Sensitivity to the CSF1R inhibitor GW-2580 was found preferentially in de novo and favorable risk patients, and resistance to GW-2580 was associated with reduced overall survival. Using flow cytometry, we discovered that CSF1R is not expressed on the majority of leukemic blasts but instead on a subpopulation of supportive cells. Comparison of CSF1R-expressing cells in AML versus healthy donors by mass cytometry (CyTOF) revealed the expression of unique cell-surface markers. The quantity of CSF1R-expressing cells correlated with GW-2580 sensitivity. Exposure of primary AML patient samples to a panel of recombinant cytokines revealed that CSF1R inhibitor sensitivity correlated with a growth response to CSF1R ligand, CSF1, and other cytokines, including HGF, an alternative growth factor. The addition of CSF1 increased the secretion of HGF and other cytokines in conditioned media from AML patient samples, while adding GW-2580 reduced their secretion. In untreated cells, HGF levels correlated significantly with GW-2580 sensitivity. Finally, recombinant HGF and HS-5-conditioned media rescued cell viability after GW-2580 treatment in AML patient samples. Our results suggest that CSF1R-expressing cells support the bulk leukemia population through the secretion of HGF and other cytokines. This study identifies CSF1R as a novel therapeutic target of AML and provides a mechanism of paracrine cytokine/growth factor signaling in this disease.
Chen, Y., Lakshmikanth, T., Olin, A. et al. "CSF1R inhibitors exhibit anti-tumor activity in acute myeloid leukemia by blocking paracrine signals from support cells" Blood (2018): pii: blood-2018-03-838946