Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as prednisone poor responders (PPR), have poorer outcome than do the other pediatric T-ALL patients receiving a high-risk adapted therapy. Because glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to improving the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled; thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches. We first identified, by reverse-phase protein arrays, the lymphocyte cell-specific protein-tyrosine kinase (LCK) as aberrantly activated in PPR patients. We showed that LCK inhibitors, such as dasatinib, bosutinib, nintedanib, and WH-4-023, are able to induce cell death in GC-resistant T-ALL cells, and remarkably, cotreatment with dexamethasone is able to reverse GC resistance, even at therapeutic drug concentrations. This was confirmed by specific LCK gene silencing and ex vivo combined treatment of cells from PPR patient-derived xenografts. Moreover, we observed that LCK hyperactivation in PPR patients upregulates the calcineurin/nuclear factor of activated T cells signaling triggering to interleukin-4 (IL-4) overexpression. GC-sensitive cells cultured with IL-4 display an increased resistance to dexamethasone, whereas the inhibition of IL-4 signaling could increase GC-induced apoptosis in resistant cells. Treatment with dexamethasone and dasatinib also impaired engraftment of leukemia cells in vivo. Our results suggest a quickly actionable approach to supporting conventional therapies and overcoming GC resistance in pediatric T-ALL patients.

中文翻译：

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小儿 T 细胞急性淋巴细胞白血病中的 LCK 抑制可逆转糖皮质激素抵抗

小儿 T 急性淋巴细胞白血病 (T-ALL) 患者通常对糖皮质激素 (GC) 治疗表现出抵抗力。这些患者被归类为泼尼松不良反应者 (PPR)，与其他接受高风险适应疗法的儿科 T-ALL 患者相比，其预后较差。由于在治疗的所有不同阶段都向 ALL 患者施用糖皮质激素，因此 GC 耐药性是改善这些患者预后的重要挑战。抵抗的机制尚未完全解开；因此，我们的研究重点是识别失调的信号通路，以指出新的靶向方法。我们首先通过反相蛋白质阵列确定了淋巴细胞特异性蛋白酪氨酸激酶 (LCK) 在 PPR 患者中异常激活。我们发现 LCK 抑制剂，例如达沙替尼、博舒替尼、尼达尼布和 WH-4-023，能够诱导 GC 抗性 T-ALL 细胞的细胞死亡，并且值得注意的是，与地塞米松联合治疗能够逆转 GC 抗性，即使在治疗药物浓度下也是如此。这通过特定的 LCK 基因沉默和来自 PPR 患者异种移植物的细胞的离体联合治疗得到证实。此外，我们观察到 PPR 患者的 LCK 过度激活上调激活的 T 细胞信号传导的钙调神经磷酸酶/核因子，从而触发白细胞介素 4 (IL-4) 过表达。用 IL-4 培养的 GC 敏感细胞对地塞米松的耐药性增加，而 IL-4 信号传导的抑制可能会增加耐药细胞中 GC 诱导的细胞凋亡。用地塞米松和达沙替尼治疗也会损害体内白血病细胞的植入。