Credit: Lara Crow/NPG

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in several cancer types and result in increased levels of the oncometabolite 2-hydroxyglutarate (2-HG), which has been implicated in tumorigenesis and thus represents a therapeutic target. However, mutant IDH1 is also known to dysregulate other metabolic pathways. A study in Cancer Cell reports that the growth of some IDH1-mutant cancers is insensitive to 2-HG loss and instead depends on the addiction of these cells to NAD+, a metabolic vulnerability that can be targeted by drugs that are already in clinical trials.

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.

Having identified a metabolic vulnerability in IDH1-mutant cells, the authors went on to demonstrate the in vivo efficacy of NAD+ depletion in immunocompromised mice bearing IDH1-mutant xenograft tumours; NAMPT inhibitor treatment significantly reduced tumour growth in a heterotopic model and significantly prolonged survival in an orthotopic model.

the preclinical efficacy of making addicted cells 'go cold turkey'

In summary, this study reveals NAD+ addiction as a previously unknown metabolic vulnerability in a proportion of IDH1-mutant cancers and demonstrates the preclinical efficacy of making addicted cells 'go cold turkey'. Notably, NAD+-depleting NAMPT inhibitors are already in clinical trials for other cancer types and so could be readily repurposed for use in IDH1-mutant cancers.