VPS34-IN1 potentiates STING-dependent activation in human CAL-1 cells.

Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been previously suggested as a potential therapeutic approach for treating certain cancers, our findings indicate that it has minimal cytotoxic effects on the leukemic blastic plasmacytoid dendritic cell neoplasm (BPDCN) CAL-1. However, we also found that VPS34-IN1 interferes with the function of this plasmacytoid dendritic cell (pDC) line, by inhibiting Toll-like receptor (TLR)7 signaling. In contrast, VPS34-IN1 triggers activation of the stimulator of interferon genes (STING) and significantly enhances cellular response to the STING agonist 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP) with increased expression of type I interferons (IFNs). Inhibition of protein synthesis by VPS34-IN1 appears to be central to this synergy with STING activation. Thus, despite their limited toxicity toward different cancer lines, VPS34-IN1 may represent a promising compound to promote expression of type I IFNs and thus antitumoral immunity.