MEK1 Inhibitor Selumetinib Sensitizes Precursor B-Cell Acute Lymphoblastic Leukemia Cells (B-ALL) to Dexamethasone through Modulation of mTOR Activity and Stimulation of Autophagy

Glucocorticoids (GC) have been used for decades in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) in children and adults. Induction of apoptosis is thought to be the principal effector mechanism of GC9s action, but recent studies highlight the role of autophagy upstream of apoptotic cell death (Laane et al 2009). Resistance to GCs is a major adverse prognostic factor, however the molecular mechanisms leading to GC resistance are not completely understood. Herein, we sought to elucidate the molecular mechanisms driving GC-resistance in precursor B-cell acute lymphoblastic leukemia cells and in vitro characterize the therapeutic potential of targeted intervention in these mechanisms. To identify molecular mechanisms involved in GC resistance, we performed gene set enrichment analysis of gene expression profiles GC-sensitive and -resistant B-ALL blasts using publicly available datasets and GenePattern program. Resistant cells exhibited significantly higher expression of MAPK/ERK pathway components (p Disclosures No relevant conflicts of interest to declare.