Despite potently reducing 2-HG levels in tumour cells, exposure to a specific inhibitor of mutant IDH1 (IDH1i) did not inhibit the in vitro growth of eight IDH1-mutant cell lines derived from three different cancer types or the in vivo growth of an orthotopically transplanted IDH1-mutant glioblastoma (MGG152) cell line. Using an unbiased systematic approach, the authors screened the metabolic profiles of MGG152 cells after both short-term and long-term IDH1i treatment in vitro and identified metabolites for which levels were significantly altered by IDH1i. These data highlighted the NAD+/NADH cycling pathway, and further experiments demonstrated that IDH1i treatment significantly increased NAD+ levels in MGG152 cells and other IDH1-mutant cell lines. In addition, inhibiting the rate-limiting enzyme of the NAD+ salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), in IDH1-mutant cell lines potently reduced cell viability in an NAD+-dependent manner.
IDH1-mutant cell lines showed lower basal intracellular NAD+ levels than IDH1 wild-type cells, which the authors hypothesized could enhance sensitivity to NAMPT inhibition. Cellular NAD+ pools are maintained by both the NAMPT salvage pathway and an alternative pathway that is rate-limited by nicotinate phosphoribosyltransferase 1 (NAPRT1). The authors found that expression of NAPRT1, but not that of NAMPT, correlated with cellular sensitivity to NAMPT inhibition, and they showed, using a tetracycline-inducible system, that mutant IDH1 expression significantly decreased levels of NAD+ and NAPRT1. This suggested that suppression of the NAPRT1-mediated alternative salvage pathway in IDH1-mutant cells renders them vulnerable to further NAD+ depletion through NAMPT inhibition. Indeed, NAPRT1 overexpression rescued IDH1-mutant cells from the effects of NAMPT inhibition.
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