Edwards V David K, Sweeney David Tyler, Ho Hibery, Eide Christopher A, Rofelty Angela, Agarwal Anupriya, Liu Selina Qiuying, Danilov Alexey V, Lee Patrice, Chantry David, McWeeney Shannon K, Druker Brian J, Tyner Jeffrey W, Spurgeon Stephen E, Loriaux Marc M
Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
Division of Hematology & Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.
Oncotarget. 2018 May 15;9(37):24576-24589. doi: 10.18632/oncotarget.25191.
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.
在许多恶性肿瘤中，肿瘤微环境包含表达集落刺激因子1受体（CSF1R）的支持性单核细胞/巨噬细胞，它们可促进肿瘤细胞存活。对于慢性淋巴细胞白血病（CLL），这些支持性单核细胞/巨噬细胞被称为类护士细胞（NLCs），尽管针对CLL的CSF1R选择性小分子抑制剂的潜在有效性尚未得到充分研究。在此，我们展示了两种CSF1R抑制剂GW - 2580和ARRY - 382在原发性CLL患者样本中的临床前活性。我们观察到至少25%的CLL样本对CSF1R抑制剂表现出亚微摩尔敏感性。在具有不同遗传和临床背景的样本中均观察到了这种敏感性，尽管白细胞计数较高和单核细胞百分比增加与敏感性增加相关。优先消耗表达CD14的单核细胞会优先降低对CSF1R抑制剂敏感的样本中的活力，并且在长期培养条件下用CSF1R抑制剂处理样本可消除NLCs的存在。这些结果表明，CSF1R小分子抑制剂靶向CLL微环境中表达CD14的单核细胞，从而剥夺白血病细胞的外在支持信号。此外，观察到CSF1R抑制剂与idelalisib或ibrutinib（两种目前破坏肿瘤细胞内在B细胞受体信号传导的CLL疗法）联合使用时具有显著的协同作用。这些发现支持同时靶向支持性NLCs和CLL细胞的概念，并证明了这种联合疗法的潜在临床应用价值。
