NAD Metabolic Dependency Determines Therapeutic Sensitivity in Cancer

NAD is a small-molecule cofactor for a variety of cellular functions such as oxidative phosphorylation, epigenetic regulation, and DNA damage repair. Successful targeting of dysregulated NAD biosynthesis in cancer has proven difficult in part due to unknown mechanisms that determine which of the many NAD biosynthetic pathways are utilized. Chowdhry and colleagues analyzed over 7,000 tumor and 2,600 normal-matched samples and observed tissue-specific copy-number and expression changes of NAD biosynthetic pathway genes. Gene amplification of the Preiss-Handler (PH) NAD biosynthetic pathway enzymes nicotinamide phosphoribosyltransferase (NAPRT) and NAD synthetase 1 (NADSYN1) were prevalent across many cancer types, and depletion of NAPRT or NADSYN1 from PH-amplified cancer cell lines induced cell death. By contrast, non–PH-amplified cancer cells were exclusively dependent on the salvage pathway for NAD synthesis and its rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Non–PH-amplified cancer cells were dependent on a c-MYC–regulated upstream enhancer of NAMPT to maintain intracellular NAD levels and cell survival. Inducible depletion of NAPRT or NADSYN1 in PH-amplified ovarian tumor xenografts induced tumor cell death, resulting in complete and durable tumor regression. However, depletion of NAMPT in salvage pathway-dependent tumor xenografts resulted in only a modest decrease in tumor proliferation and growth, as only dual depletion of both NAMPT and the salvage pathway enzyme nicotinamide riboside kinase 1 (NMRK1) resulted in tumor cell death and complete and durable tumor regression. Pharmacologic inhibition of NADSYN1 impaired growth and reduced NAD levels in PH-amplified cancer cell lines and NAPRT-amplified tumor xenografts. Inhibition of NAMPT slowed growth of salvage pathway–dependent cancer cells in vitro and in vivo, but depletion of NMRK1 lowered the NAMPT inhibitor dose needed to inhibit growth. Collectively, these data show that cancer cells become addicted to NAD biosynthetic pathways in a tissue-specific manner and demonstrate the therapeutic potential of pharmacologically targeting these pathways.

Chowdhry S, Zanca C, Rajkumar U, Koga T, Diao Y, Raviram R, et al. NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling. Nature 2019 Apr 24 [Epub ahead of print].

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