Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC, Canada.
National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, School of Life Sciences, Jilin University, Jilin, China.
Blood. 2021 Jul 1;137(26):3641-3655. doi: 10.1182/blood.2020007651.
The abundance of genetic abnormalities and phenotypic heterogeneities in acute myeloid leukemia (AML) poses significant challenges to the development of improved treatments. Here, we demonstrated that a key growth arrest-specific gene 6/AXL axis is highly activated in cells from patients with AML, particularly in stem/progenitor cells. We developed a potent selective AXL inhibitor that has favorable pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation (PDX) models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in PDX models. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition, alone or in combination with venetoclax, potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells and shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. Inhibition of AXL or BCL-2 also differentially targets key signaling proteins to synergize in leukemic cell killing. These findings have a direct translational impact on the treatment of AML and other cancers with high AXL activity.
急性髓系白血病（AML）中遗传异常和表型异质性的丰富性给改进治疗方法的发展带来了重大挑战。在这里，我们证明了关键的生长停滞特异性基因 6/AXL 轴在 AML 患者的细胞中高度激活，特别是在干细胞/祖细胞中。我们开发了一种有效的选择性 AXL 抑制剂，具有良好的药物特性和针对 AML 临床前患者来源异种移植（PDX）模型的疗效。重要的是，AXL 的抑制使 AML 干细胞/祖细胞对 venetoclax 治疗敏感，在体外和 PDX 模型中具有强烈的协同作用。从机制上讲，单细胞 RNA 测序和功能验证研究表明，AXL 抑制，单独或与 venetoclax 联合使用，可能靶向 AML 干细胞/祖细胞的固有代谢脆弱性，并显示出独特的转录组谱，抑制线粒体氧化磷酸化。AXL 或 BCL-2 的抑制也可靶向关键信号蛋白以协同杀伤白血病细胞。这些发现对具有高 AXL 活性的 AML 和其他癌症的治疗具有直接的转化意义。
