TMET-19. Targeting NQO1 and the NAD+ Salvage Pathway: A Novel Therapeutic Strategy for Glioblastoma

Abstract A series of genes involved in NAD+ metabolism is over expressed in glioblastoma (GBM). One of these genes, NADPH quinone oxidoreductase (NQO1), plays a role in managing endogenous oxidative stress response and has been reported to be overexpressed in other malignancies. NQO1 expressing cancer cells may be selectively targeted by NQO1-bioactivatable compounds including the naphthoquinone β-lapachone (β-lap), leading to oxidative stress and cell death. We first identified NQO1-expression status in the U87 GBM cell line, multiple patient-derived xenograft (PDX) GBM cell lines, and normal human astrocytes (NHA). Cells were then accessed for sensitivity to NQO1 targeting compounds including β-lap. Dose-response studies, NAD+ quantification, and immunoblot were utilized to evaluate the link between NAD+ synthesis and β-lap toxicity. We demonstrate NQO1 to be highly expressed in multiple GBM cell lines and β-lap induces selective cytotoxicity in these cells while sparing low NQO1-expressing cells including NHA. We show β-lap induces acute NAD+ depletion, however high NQO1-expressing GBM cells may regenerate NAD+ and evade β-lap toxicity. We identified the NAD+ salvage pathway to be active in GBM and the primary pathway responsible for NAD+ regeneration in β-lap treated GBM. We demonstrate that targeting the NAD+ salvage pathway with the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 prevents NAD+ regeneration after β-lap exposure and enhances β-lap cytotoxicity in NQO1-expressing GBM. These findings suggest that identifying and targeting NQO1-expressing GBM with NQO1 bioactivatable compounds in conjunction with NAMPT-inhibitors is a promising therapeutic strategy for the treatment of GBM.