携带 FMS 相关受体酪氨酸激酶 3 内部串联重复 (FLT3/ITD) 突变的急性髓系白血病 (AML) 患者预后较差，FLT3 酪氨酸激酶抑制剂 (TKI) 的治疗受到耐药机制的阻碍。其中一种机制被称为适应性抵抗，其中下游信号通路在初始抑制后重新激活。过去的研究表明，FLT3/ITD 细胞通过在持续抑制 FLT3 的 24 小时内重新激活细胞外信号调节激酶 (ERK) 信号而经历适应性抵抗。我们研究了导致这种 ERK 重新激活的机制，并假设靶向酪氨酸蛋白激酶受体 UFO (AXL)（另一种与癌症抵抗力有关的受体酪氨酸激酶）可能会克服适应性 ERK 重新激活。实验表明，在开始 TKI 治疗几小时后，FLT3/ITD 细胞系中的 AXL 就会上调并被激活。 AXL 抑制与 FLT3 抑制相结合，可减少 ERK 信号反弹，并比单独使用任一治疗发挥更大的抗白血病作用。最后，我们观察到患者样本中发生 TKI 诱导的 AXL 上调，并且 AXL 和 FLT3 的联合抑制增加了我们体内模型中的疗效。总而言之，这些数据表明 AXL 在 FLT3/ITD AML 的适应性抵抗中发挥作用，并且 AXL 和 FLT3 联合抑制可能会改善 FLT3/ITD AML 患者的预后。© 2024 作者。约翰·威利出版的《分子肿瘤学》

Acute myeloid leukemia (AML) patients with the FMS-related receptor tyrosine kinase 3 internal tandem duplication (FLT3/ITD) mutation have a poorer prognosis, and treatment with FLT3 tyrosine kinase inhibitors (TKIs) has been hindered by resistance mechanisms. One such mechanism is known as adaptive resistance, in which downstream signaling pathways are reactivated after initial inhibition. Past work has shown that FLT3/ITD cells undergo adaptive resistance through the reactivation of extracellular signal-regulated kinase (ERK) signaling within 24 h of sustained FLT3 inhibition. We investigated the mechanism(s) responsible for this ERK reactivation and hypothesized that targeting tyrosine-protein kinase receptor UFO (AXL), another receptor tyrosine kinase that has been implicated in cancer resistance, may overcome the adaptive ERK reactivation. Experiments revealed that AXL is upregulated and activated in FLT3/ITD cell lines mere hours after commencing TKI treatment. AXL inhibition combined with FLT3 inhibition to decrease the ERK signal rebound and to exert greater anti-leukemia effects than with either treatment alone. Finally, we observed that TKI-induced AXL upregulation occurs in patient samples, and combined inhibition of both AXL and FLT3 increased efficacy in our in vivo models. Taken together, these data suggest that AXL plays a role in adaptive resistance in FLT3/ITD AML and that combined AXL and FLT3 inhibition might improve FLT3/ITD AML patient outcomes.© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.