Targeting AXL Kinase Uniquely Sensitizes Therapy-Insensitive Leukemic Stem and Progenitor Cells to Venetoclax Treatment in Acute Myeloid Leukemia

The abundance of genetic abnormalities and phenotypic heterogeneities in AML pose significant challenges to developing improved treatments. Here we demonstrated that a key GAS6/AXL axis is highly activated in AML patient cells, particularly in leukemic stem cells. We developed a potent, selective AXL inhibitor that has excellent pharmaceutical properties and efficacy against preclinical patient-derived xenotransplantation models of AML. Importantly, inhibition of AXL sensitized AML stem/progenitor cells to venetoclax treatment, with strong synergistic effects in vitro and in vivo. Mechanistically, single-cell RNA-sequencing and functional validation studies uncovered that AXL inhibition or in combination with venetoclax potentially targets intrinsic metabolic vulnerabilities of AML stem/progenitor cells, which shows a distinct transcriptomic profile and inhibits mitochondrial oxidative phosphorylation. These findings have direct translational impact on the treatment of AML and other cancers with high AXL activity.EGA study EGAS00001004663

急性髓系白血病（Acute Myeloid Leukemia, AML）中广泛存在的遗传异常与表型异质性，为开发更优化的治疗方案带来了重大挑战。本研究证实，关键的GAS6/AXL信号轴在AML患者细胞，尤其是白血病干细胞中呈高度激活状态。我们开发了一种强效且高选择性的AXL抑制剂，该抑制剂具备优异的药学特性，且对AML患者来源的临床前异种移植模型具有显著疗效。尤为重要的是，抑制AXL可使AML干/祖细胞对维奈克拉（venetoclax）治疗产生敏感性，在体外与体内实验中均展现出强大的协同效应。从机制层面分析，单细胞RNA测序（single-cell RNA-sequencing）与功能验证实验揭示，单独抑制AXL或联合维奈克拉治疗，可靶向作用于AML干/祖细胞固有的代谢脆弱性：这类细胞具有独特的转录组特征，且治疗可阻断线粒体氧化磷酸化过程。上述研究结果对AML及其他AXL高活性癌症的临床治疗具有直接的转化应用价值。本研究对应欧洲基因组表型档案（EGA）研究项目EGAS00001004663。