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.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, with nearly 19,000 new cases reported annually in the United States [1]
We observed that a proportion of chronic lymphocytic leukemia (CLL) specimens showed sensitivity to these selective CSF1R inhibitors, with 25.9% (51/197) and 27.5% (36/131) of specimens showing submicromolar IC50s for GW-2580 and ARRY-382, respectively (Figure 1C-1D)
Previous genomic analyses of CLL patients have identified no mutations in CSF1R [27, 28], nor is CSF1R significantly overexpressed in CLL compared to healthy monocytes
Summary
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, with nearly 19,000 new cases reported annually in the United States [1]. The disease is characterized by an accumulation of small mature B-lymphocytes in the lymph nodes, bone marrow and peripheral blood. CLL is predominantly an indolent disease; around 25% of patients progress rapidly [2]. Therapy is generally reserved for patients with symptomatic disease and, until recently, has largely relied on chemo-immunotherapy combination regimens. Introduction of novel targeted therapies that inhibit B-cell receptor (BCR) signaling—such as ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, and idelalisib, a phosphatidylinositol-3-kinase delta isoform specific (PI3kδ) inhibitor—have dramatically improved patient outcomes and treatment options [3]. CLL remains incurable with these classical treatments, and most patients succumb to the disease or its complications
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