Phosphatidylinositol 3‐kinase inhibition potentiates glucocorticoid response in B‐cell acute lymphoblastic leukemia

Abstract

Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains fatal in around 20% of cases. Hence, novel targeted therapies are needed for patients with poor prognosis. Glucocorticoids (GCs) are drugs commonly administrated for B-ALL treatment. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway is frequently observed in B-ALL and contributes to GC-resistance. Here, we analyzed for the first time to our knowledge, the therapeutic potential of pan and isoform-selective PI3K p110 inhibitors, alone or combined with dexamethasone (DEX), in B-ALL leukemia cell lines and patient samples. We found that a pan PI3K p110 inhibitor displayed the most powerful cytotoxic effects in B-ALL cells, by inducing cell cycle arrest and apoptosis. Both a pan PI3K p110 inhibitor and a dual γ/δ PI3K p110 inhibitor sensitized B-ALL cells to DEX by restoring nuclear translocation of the GC receptor and counteracted stroma-induced DEX-resistance. Finally, gene expression analysis documented that, on one hand the combination consisting of a pan PI3K p110 inhibitor and DEX strengthened the DEX-induced up- or down-regulation of several genes involved in apoptosis, while on the other, it rescued the effects of genes that might be involved in GC-resistance. Overall, our findings strongly suggest that PI3K p110 inhibition could be a promising strategy for treating B-ALL patients by improving GC therapeutic effects and/or overcoming GC-resistance.

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

“…It is well established that the PI3K/Akt/mTOR pathway is aberrantly activated in approximately 60% of T‐ALL patients (Silva et al, ) and correlates with a poor outcome (Bongiovanni et al, ). Our group previously showed that PI3K inhibition displayed strong cytotoxic effects on both ALL cell lines and primary cells, demonstrating that targeting PI3K could be an attractive strategy for treating ALLs (Bressanin et al, ; Evangelisti et al, ; Lonetti et al, ; Lonetti et al, ). This therapeutic approach for ALL has been supported by several clinical trials of PI3K inhibitors.…”

“…Western blot analysis was performed as previously described (Evangelisti et al, ). Cells were lysed using M‐PER Mammalian Protein Extraction Reagent supplemented with the Protease and Phosphatase Inhibitor Cocktail (Thermo Fisher Scientific Inc., Rockford, IL).…”

“…Western blot analysis was performed as previously described (Evangelisti et al, 2018a). Cells were lysed using M-PER Mammalian…”

Targeting the phosphatidylinositol 3‐kinase/Akt/mechanistic target of rapamycin signaling pathway in B‐lineage acute lymphoblastic leukemia: An update

“…We found that ZSTK‐474, a pan p110 PI3K inhibitor, displayed the most powerful cytotoxic effects in B‐ALL cells. However, both ZSTK‐474 and the dual γ/δ p110 PI3K inhibitor IPI‐145 (Duvelisib), sensitized B‐ALL cells to DEX by restoring nuclear translocation of the GC receptor and counteracted stromal cell‐induced DEX‐resistance (Evangelisti et al, ). Moreover, we performed gene expression analysis which demonstrated that the combination consisting of ZSTK‐474 and DEX strengthened the DEX‐induced up‐ or downregulation of several genes involved in apoptosis, however the combination also rescued the effects of genes that might be involved in GC‐resistance.…”

Roles and clinical implications of microRNAs in acute lymphoblastic leukemia

“…ALL is most commonly a pediatric malignancy, but a significant percentage of cases occurs also in adults (Evangelisti et al, ). Although pediatric ALL is highly responsive to chemotherapy, relapse occurs in approximately 25% of children (Pica et al, ).…”