PI3Kδ inhibition potentiates glucocorticoids in B-ALL by decreased receptor phosphorylation and enhanced gene regulation

by Selleckchem | Mar 19 2023

Glucocorticoids, including dexamethasone and prednisone, are key components of therapy for B-lymphoblastic leukemia (B-ALL) that work through the glucocorticoid receptor (GR). However, glucocorticoids are not effective for all patients, leading to poor outcomes, and their use is hampered by undesirable toxic effects. We have shown that inhibition of PIK3δ, the leukocyte-restricted delta isoform of the catalytic subunit of phosphoinositide 3-kinase, is a promising way to specifically enhance the effect of glucocorticoids in B-ALL, with the potential to improve outcomes without increasing toxicities. Here, we show that the PI3Kδ inhibitor idelalisib potentiates both prednisolone and dexamethasone in B-ALL cell lines and most primary patient specimens, particularly at sub-saturating doses of glucocorticoids. Potentiation is explained in part by a widespread enhancement of glucocorticoid-induced gene regulation, including of effector genes that drive B-ALL cell death. Idelalisib causes a reduction in phosphorylation of GR at S203 and S226, and ablation of these phospho-acceptor sites enhances glucocorticoid potency. Because phosphorylation of S226 inhibits GR DNA binding, we propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing inhibitory GR phosphorylation and enhancing DNA binding and downstream gene regulation. These studies provide a pre-clinical and mechanistic rationale for clinical application of PI3Kδ inhibitors in combination with glucocorticoids for treatment of B-ALL.

Comments：

The statement describes research that shows the potential for combining glucocorticoids with a PI3Kδ inhibitor called idelalisib to improve outcomes in the treatment of B-lymphoblastic leukemia (B-ALL). The research indicates that the inhibitor enhances the effectiveness of glucocorticoids in B-ALL cell lines and primary patient specimens, particularly at sub-saturating doses of glucocorticoids. The enhanced effectiveness is explained in part by a widespread enhancement of glucocorticoid-induced gene regulation, including of effector genes that drive B-ALL cell death.

The research also found that idelalisib causes a reduction in the phosphorylation of the glucocorticoid receptor (GR) at S203 and S226. Phosphorylation of S226 inhibits GR DNA binding, and decreasing inhibitory GR phosphorylation enhances DNA binding and downstream gene regulation. These findings suggest that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL by decreasing inhibitory GR phosphorylation and enhancing DNA binding and downstream gene regulation.

Overall, the research provides a pre-clinical and mechanistic rationale for the clinical application of PI3Kδ inhibitors in combination with glucocorticoids for the treatment of B-ALL. By enhancing the effectiveness of glucocorticoids, this combination therapy could improve outcomes for patients with B-ALL without increasing toxicities associated with glucocorticoid therapy.