Antileukemic activity of the VPS34-IN1 inhibitor in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis. Vacuolar protein sorting 34 (VPS34) is a member of the phosphatidylinositol-3-kinase lipid kinase family that controls the canonical autophagy pathway and vesicular trafficking. Using a recently developed specific inhibitor (VPS34-IN1), we found that VPS34 inhibition induces apoptosis in AML cells but not in normal CD34+ hematopoietic cells. Complete and acute inhibition of VPS34 was required for the antileukemic activity of VPS34-IN1. This inhibitor also has pleiotropic effects against various cellular functions related to class III PI3K in AML cells that may explain their survival impairment. VPS34-IN1 inhibits basal and l-asparaginase-induced autophagy in AML cells. A synergistic cell death activity of this drug was also demonstrated. VPS34-IN1 was additionally found to impair vesicular trafficking and mTORC1 signaling. From an unbiased approach based on phosphoproteomic analysis, we identified that VPS34-IN1 specifically inhibits STAT5 phosphorylation downstream of FLT3-ITD signaling in AML. The identification of the mechanisms controlling FLT3-ITD signaling by VPS34 represents an important insight into the oncogenesis of AML and could lead to new therapeutic strategies.

PIK3C3 Inhibition Promotes Sensitivity to Colon Cancer Therapy by Inhibiting Cancer Stem Cells

“…Recent studies have shown the potential of inhibiting VPS34-activity as a highly potent means for inhibiting autophagy [ 27 ]. Hence, based on the recently published reports focusing on VPS34 inhibition [ 28 , 29 , 30 ] we synthesized a highly potent and specific VPS34 inhibitor that was potent, selective and potentially effective in vivo [ 31 ], and named it 36-077. The chemical structure of 36-077 is presented in Figure 3 A and the synthesis route has been described in the Figure S1 and Section 2 .…”

Autophagy modulation as a potential targeted cancer therapy: From drug repurposing to new drug development

“…VPS34‐IN1 is another specific inhibitor of VPS34 with 25 nM of IC 50. 31 VPS34‐IN1 induces apoptosis in acute myeloid leukemia (AML) without affecting normal hematopoietic cells 30 …”

The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer

“…VPS34-IN1 inhibits PIK3C3 with a 25 nM IC50 in vitro but does not significantly inhibit the activity of class I and class II PI3Ks [132]. VPS34-IN1 has been reported to inhibit tumor growth or cell survival in HCC [106], glioblastoma [113], and myeloid leukemia [130] when used alone and to synergize with ZSTK474 [106], vemurafenib [113], L-asparaginase [130], and ceritinib [11].…”

“…VPS34-IN1 was found to induce apoptosis in nine acute myeloid leukemia (AML) cell lines but not in normal CD34+ hematopoietic cells [130]. VPS34-IN1 inhibits basal and Lasparaginase-induced autophagy in AML cells and is synergistic with L-asparaginase [130].…”

“…VPS34-IN1 was found to induce apoptosis in nine acute myeloid leukemia (AML) cell lines but not in normal CD34+ hematopoietic cells [130]. VPS34-IN1 inhibits basal and Lasparaginase-induced autophagy in AML cells and is synergistic with L-asparaginase [130]. In MOLM-14 leukemic cells, VPS34-IN1 was also found to impair vesicular trafficking and mTORC1 signaling and inhibit STAT5 phosphorylation downstream of FLT3-ITD signaling [130].…”