Background/Objectives: Acute myeloid leukemia (AML) is an aggressive neoplasm. Although most patients respond to induction therapy, they commonly relapse due to recurrent disease in the bone marrow microenvironment (BMME). So, the disruption of the BMME, releasing tumor cells into the peripheral circulation, has therapeutic potential. Methods: Using both primary donor AML cells and cell lines, we developed an in vitro co-culture model of the AML BMME. We used this model to identify the most effective agent(s) to block AML cell adherence and reverse adhesion-mediated treatment resistance. Results: We identified that anti-CD44 treatment significantly increased the efficacy of cytarabine. However, some AML cells remained adhered, and transcriptional analysis identified focal adhesion kinase (FAK) signaling as a contributing factor; the adhered cells showed elevated FAK phosphorylation that was reduced by the FAK inhibitor, defactinib. Importantly, we demonstrated that anti-CD44 and defactinib were highly synergistic at diminishing the adhesion of the most primitive CD34highAML cells in primary autologous co-cultures. Conclusions: Taken together, we identified anti-CD44 and defactinib as a promising therapeutic combination to release AML cells from the chemoprotective AML BMME. As anti-CD44 is already available as a recombinant humanized monoclonal antibody, the combination of this agent with defactinib could be rapidly tested in AML clinical trials.
背景/目的：急性髓系白血病（AML）是一种侵袭性肿瘤。尽管大多数患者对诱导治疗有反应，但由于骨髓微环境（BMME）中的疾病复发，患者常出现复发。因此，破坏BMME、将肿瘤细胞释放至外周循环具有治疗潜力。方法：利用原代供体AML细胞及细胞系，我们建立了AML BMME的体外共培养模型。通过该模型，我们筛选出能最有效阻断AML细胞黏附并逆转黏附介导治疗耐药性的药物。结果：研究发现抗CD44治疗能显著增强阿糖胞苷的疗效。然而，部分AML细胞仍保持黏附状态，转录组分析显示黏着斑激酶（FAK）信号通路是重要影响因素；黏附细胞表现出FAK磷酸化水平升高，而FAK抑制剂defactinib可降低该磷酸化水平。重要的是，我们在原代自体共培养体系中证实，抗CD44与defactinib在减少最原始CD34高表达AML细胞黏附方面具有高度协同作用。结论：综合而言，抗CD44与defactinib的组合疗法有望将AML细胞从具有化疗保护作用的AML BMME中释放出来。由于抗CD44已作为重组人源化单克隆抗体上市，该药物与defactinib的联合方案可快速进入AML临床试验验证阶段。
肿瘤(癌症)患者之家