Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples

David K. Edwards V, David Tyler Sweeney, Hibery Ho, Christopher A. Eide, Angela Rofelty, Anupriya Agarwal, Selina Qiuying Liu, Alexey V. Danilov, Patrice Lee, David Chantry, Shannon K. McWeeney, Brian J. Druker, Jeffrey W. Tyner, Stephen E. Spurgeon, Marc M. Loriaux

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

In many malignancies, the tumor microenvironment includes CSF1R-expressing supportive monocyte/macrophages that promote tumor cell survival. For chronic lymphocytic leukemia (CLL), these supportive monocyte/macrophages are known as nurse-like cells (NLCs), although the potential effectiveness of selective smallmolecule inhibitors of CSF1R against CLL is understudied. Here, we demonstrate the preclinical activity of two inhibitors of CSF1R, GW-2580 and ARRY-382, in primary CLL patient samples. We observed at least 25% of CLL samples showed sub-micromolar sensitivity to CSF1R inhibitors. This sensitivity was observed in samples with varying genetic and clinical backgrounds, although higher white cell count and monocyte cell percentage was associated with increased sensitivity. Depleting CD14-expressing monocytes preferentially decreased viability in samples sensitive to CSF1R inhibitors, and treating samples with CSF1R inhibitors eliminated the presence of NLCs in longterm culture conditions. These results indicate that CSF1R small-molecule inhibitors target CD14-expressing monocytes in the CLL microenvironment, thereby depriving leukemia cells of extrinsic support signals. In addition, significant synergy was observed combining CSF1R inhibitors with idelalisib or ibrutinib, two current CLL therapies that disrupt tumor cell intrinsic B-cell receptor signaling. These findings support the concept of simultaneously targeting supportive NLCs and CLL cells and demonstrate the potential clinical utility of this combination.

Original languageEnglish (US)
Pages (from-to)24576-24589
Number of pages14
JournalOncotarget
Volume9
Issue number37
DOIs
StatePublished - May 15 2018

Keywords

  • Chronic lymphocytic leukemia
  • Colony-stimulating factor 1 receptor
  • Small-molecule inhibitors
  • Tumor microenvironment
  • Tumor-associated macrophages

ASJC Scopus subject areas

  • Oncology

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