Zimmerman Jessica A O, Fang Mimi, Pufall Miles A
Division of Pediatric Hematology/Oncology, Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
Cancers (Basel). 2023 Dec 27;16(1):143. doi: 10.3390/cancers16010143.
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。由于对单独糖皮质激素的反应可预测B-ALL的总体预后，增强糖皮质激素的效力应能改善治疗效果。我们之前表明，使用idelalisib抑制淋巴细胞特异性PI3Kδ可增强B-ALL细胞中的糖皮质激素活性。在此，我们发现idelalisib可增强90%的原发性B-ALL标本中的糖皮质激素效力，且在接近EC50的糖皮质激素亚饱和剂量时最为明显。增效作用与所有糖皮质激素调节基因的调节增强有关，包括驱动B-ALL细胞死亡的基因。Idelalisib可降低糖皮质激素受体（GR）在PI3Kδ/MAPK1（ERK2）靶点S203和S226处的磷酸化。这些磷酸化位点的缺失会增强对糖皮质激素的敏感性，特别是S226位点的缺失会降低协同作用。我们还表明，S226的磷酸化会降低GR在体外与DNA的亲和力。我们提出，PI3Kδ抑制可部分通过降低GR磷酸化、增加DNA结合亲和力和增强下游基因调节来提高B-ALL中糖皮质激素的疗效。这种机制以及患者标本的反应表明，idelalisib将使大多数B-ALL患者受益，但尤其对反应较差的患者，包括高危疾病患者有益。这种联合疗法对于开发毒性较小的糖皮质激素节省疗法也很有前景。
