TY - JOUR
T1 - Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples
AU - Edwards V, David K.
AU - Sweeney, David Tyler
AU - Ho, Hibery
AU - Eide, Christopher A.
AU - Rofelty, Angela
AU - Agarwal, Anupriya
AU - Liu, Selina Qiuying
AU - Danilov, Alexey V.
AU - Lee, Patrice
AU - Chantry, David
AU - McWeeney, Shannon K.
AU - Druker, Brian J.
AU - Tyner, Jeffrey W.
AU - Spurgeon, Stephen E.
AU - Loriaux, Marc M.
N1 - Funding Information:
This work was supported in part by The Leukemia & Lymphoma Society. S.E.S. and M.M.L. are supported by SWOG/Hope Foundation. J.W.T. is supported by the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research, and the National Cancer Institute (5R00CA151457-04; 1R01CA183947-01). D.K.E.V is supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1448072. A.V.D is supported by the Lymphoma Research Foundation.
Funding Information:
J.W.T. receives research support from Agios Pharmaceuticals, Array Biopharma, Aptose Biosciences, AstraZeneca, Constellation Pharmaceuticals, Genentech, Incyte, Janssen Research & Development, Seattle Genetics, and Takeda Pharmaceuticals, and is a consultant for Leap Oncology. S.E.S. receives research support from Bristol-Myers Squibb, Genentech, Janssen, Gilead, and Acerta and has received an honorarium from Gilead. AA receives research funding from CTI BioPharma. PL and DC are employed at Array Biopharma. A.V.D. Millenium Pharmaceuticals: Research Funding; Gilead Sciences Inc.: Research Funding; B.J.D.: Fred Hutchinson
Funding Information:
Special thanks to the OHSU Pathology Flow Cytometry Lab, especially Randy Eskelin, Haibo Li and Doug Higgins; and to Taylor Rowland and Cody Paiva for conducting the IGHV sequencing. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. This work was supported in part by The Leukemia & Lymphoma Society. S.E.S. and M.M.L. are supported by SWOG/Hope Foundation. J.W.T. is supported by the V Foundation for Cancer Research, the Gabrielle's Angel Foundation for Cancer Research, and the National Cancer Institute (5R00CA151457-04; 1R01CA183947-01). D.K.E.V is supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1448072. A.V.D is supported by the Lymphoma Research Foundation
Publisher Copyright:
© Edwards V et al.
PY - 2018/5/15
Y1 - 2018/5/15
N2 - 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.
AB - 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.
KW - Chronic lymphocytic leukemia
KW - Colony-stimulating factor 1 receptor
KW - Small-molecule inhibitors
KW - Tumor microenvironment
KW - Tumor-associated macrophages
UR - http://www.scopus.com/inward/record.url?scp=85046952081&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046952081&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.25191
DO - 10.18632/oncotarget.25191
M3 - Article
C2 - 29872489
AN - SCOPUS:85046952081
SN - 1949-2553
VL - 9
SP - 24576
EP - 24589
JO - Oncotarget
JF - Oncotarget
IS - 37
ER -