Oncotarget

Priority Research Papers:

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 _

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Oncotarget. 2018; 9:24576-24589. https://doi.org/10.18632/oncotarget.25191

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Abstract

David K. Edwards V1,*, David Tyler Sweeney2,*, Hibery Ho2, Christopher A. Eide2, Angela Rofelty2, Anupriya Agarwal2, Selina Qiuying Liu2, Alexey V. Danilov2, Patrice Lee3, David Chantry3, Shannon K. McWeeney4, Brian J. Druker2,5, Jeffrey W. Tyner1, Stephen E. Spurgeon2,** and Marc M. Loriaux2,**

1 Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA

2 Division of Hematology & Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA

3 Array BioPharma, Boulder, CO, USA

4 Department of Bioinformatics and Computational Biology, Oregon Health & Science University, Portland, OR, USA

5 Howard Hughes Medical Institute, Oregon Health & Science University, Knight Cancer Institute, Portland, OR, USA

* These authors have contributed equally to this work

** These authors have contributed equally to this work

Correspondence to:

Marc M. Loriaux, email:

Keywords: colony-stimulating factor 1 receptor; chronic lymphocytic leukemia; tumor-associated macrophages; tumor microenvironment; small-molecule inhibitors

Received: September 26, 2017     Accepted: March 01, 2018     Published: May 15, 2018

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 small-molecule 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 long-term 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.


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