AKT/mTORC2 Inhibition Activates FOXO1 Function in CLL Cells Reducing B-Cell Receptor-Mediated Survival.

ABSTRACT:

Purpose

To determine whether inhibition of mTOR kinase-mediated signaling represents a valid therapeutic approach for chronic lymphocytic leukemia (CLL).

Experimental design

Stratification of mTOR activity was carried out in patients with primary CLL samples and an aggressive CLL-like mouse model. The potency of dual mTOR inhibitor AZD8055 to induce apoptosis in primary CLL cells was assessed in the presence/absence of B-cell receptor (BCR) ligation. Furthermore, we addressed the molecular and functional impact of dual mTOR inhibition in combination with BTK inhibitor ibrutinib.

Results

Differential regulation of basal mTORC1 activity was observed in poor prognostic CLL samples, with elevated p4EBP1^T37/46 and decreased p70S6 kinase activity, suggesting that

SUBMITTER: Cosimo E 

PROVIDER: S-EPMC6398589 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature