抄録
PI3K delta (phosphatidylinositol-4,5-bisphosphate 3-kinase delta) and FLT3 (fms-related tyrosine kinase 3) are frequently activated in acute myeloid leukemia (AML) and have been implicated as potential therapeutic targets. In this report, we demonstrate that combined inhibition of PI3K delta and FLT3 exerts synergistic antitumor activity in FLT3-activated AML. Synergistic antiproliferative effects were observed in FLT3-activated MV-4-11 and EOL-1 AML cell lines, but not in FLT3-independent RS4;11 and HEL cells, as demonstrated by both pharmacological inhibition and silencing of PI3K delta/FLT3. Combined treatment with PI3K delta and FLT3 inhibitors more effectively inhibited phosphorylation of AKT and ERK (extracellular signal-regulated kinase), and induced apoptosis more efficiently than either agent alone. This synergistic effect was confirmed in hematopoietic 32D cells transfected with an FLT3-ITD (internal tandem duplication) mutant, but not FLT3 wild type. In in vivo FLT3-activated AML xenografts, a PI3K delta inhibitor combined with FLT3 inhibitor led to significantly enhanced antitumor activity compared with either agent alone, in association with simultaneous inhibition of AKT and ERK, with no additional toxicity. Importantly, the PI3K delta inhibitor CAL101 combined with FLT3 inhibitors overcame acquired drug resistance in FLT3-ITD AML cells. Thus, combined inhibition of PI3K delta and FLT3 may be a promising strategy in FLT3-activated AML, particularly for patients with FLT3-inhibitor resistant mutations.
