Glucocorticoids are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency should improve treatment. We previously showed that inhibition of the lymphoid-restricted PI3Kδ with idelalisib enhances glucocorticoid activity in B-ALL cells. Here, we show that idelalisib enhances glucocorticoid potency in 90% of primary B-ALL specimens and is most pronounced at sub-saturating doses of glucocorticoids near the EC50. Potentiation is associated with enhanced regulation of all glucocorticoid-regulated genes, including genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at PI3Kδ/MAPK1 (ERK2) targets S203 and S226. Ablation of these phospho-acceptor sites enhances sensitivity to glucocorticoids with ablation of S226 in particular reducing synergy. We also show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro. We propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. This mechanism and the response of patient specimens suggest that idelalisib will benefit most patients with B-ALL, but particularly patients with less responsive, including high-risk, disease. This combination is also promising for the development of less toxic glucocorticoid-sparing therapies.
糖皮质激素是B淋巴细胞白血病（B-ALL）治疗的基石。由于单独使用糖皮质激素的疗效可预测B-ALL的总体预后，增强糖皮质激素效力有望改善治疗效果。我们先前研究发现，使用艾代拉里斯抑制淋巴限制性PI3Kδ可增强B-ALL细胞中糖皮质激素的活性。本研究表明，艾代拉里斯在90%的原发性B-ALL样本中能增强糖皮质激素效力，这种增效作用在接近半数有效浓度（EC50）的亚饱和剂量糖皮质激素条件下最为显著。增效作用与所有糖皮质激素调控基因（包括驱动B-ALL细胞死亡的基因）的增强调控相关。艾代拉里斯可降低糖皮质激素受体（GR）在PI3Kδ/MAPK1（ERK2）靶点S203和S226位点的磷酸化。消除这些磷酸化位点可增强对糖皮质激素的敏感性，其中S226位点的消除尤其会降低协同效应。我们还发现S226位点的磷酸化会降低GR在体外与DNA的亲和力。我们认为PI3Kδ抑制剂通过降低GR磷酸化、增强DNA结合亲和力及强化下游基因调控，从而部分提升糖皮质激素在B-ALL中的疗效。该机制及患者样本的反应表明，艾代拉里斯将使大多数B-ALL患者受益，特别是对糖皮质激素反应较差（包括高危）的患者。该联合治疗方案也为开发低毒性的糖皮质激素减量疗法提供了新方向。
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