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Oncotarget. 2018 May 15;9(37):24576-24589. doi: 10.18632/oncotarget.25191. eCollection 2018 May 15.

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

Author information

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.

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.

KEYWORDS:

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

Conflict of interest statement

CONFLICTS OF INTEREST 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 Cancer Research Center: Research Funding; Bristol-Myers Squibb: Research Funding; Henry Stewart Talks: Patents & Royalties; Millipore: Patents & Royalties; Sage Bionetworks: Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis Pharmaceuticals: Research Funding; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; CTI Biosciences: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Oncotide Pharmaceuticals: Research Funding ; Roche TCRC, Inc.: Consultancy, Membership on an entity’s Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; ARIAD: Research Funding; Aptose Therapeutics, Inc (formerly Lorus): Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. All other researchers have no relevant conflicts to disclose.

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