NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling

Sudhir Chowdhry, Ciro Zanca, Utkrisht Rajkumar, Tomoyuki Koga, Yarui Diao, Ramya Raviram, Feng Liu, Kristen Turner, Huijun Yang, Elizabeth Brunk, Junfeng Bi, Frank Furnari, Vineet Bafna, Bing Ren and Paul S. Mischel ()
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Sudhir Chowdhry: University of California at San Diego
Ciro Zanca: University of California at San Diego
Utkrisht Rajkumar: University of California at San Diego
Tomoyuki Koga: University of California at San Diego
Yarui Diao: Duke University School of Medicine
Ramya Raviram: University of California at San Diego
Feng Liu: National Research Center for Translational Medicine
Kristen Turner: University of California at San Diego
Huijun Yang: University of California at San Diego
Elizabeth Brunk: University of California at San Diego
Junfeng Bi: University of California at San Diego
Frank Furnari: University of California at San Diego
Vineet Bafna: University of California at San Diego
Bing Ren: University of California at San Diego
Paul S. Mischel: University of California at San Diego

Nature, 2019, vol. 569, issue 7757, 570-575

Abstract: Abstract Precision oncology hinges on linking tumour genotype with molecularly targeted drugs1; however, targeting the frequently dysregulated metabolic landscape of cancer has proven to be a major challenge2. Here we show that tissue context is the major determinant of dependence on the nicotinamide adenine dinucleotide (NAD) metabolic pathway in cancer. By analysing more than 7,000 tumours and 2,600 matched normal samples of 19 tissue types, coupled with mathematical modelling and extensive in vitro and in vivo analyses, we identify a simple and actionable set of ‘rules’. If the rate-limiting enzyme of de novo NAD synthesis, NAPRT, is highly expressed in a normal tissue type, cancers that arise from that tissue will have a high frequency of NAPRT amplification and be completely and irreversibly dependent on NAPRT for survival. By contrast, tumours that arise from normal tissues that do not express NAPRT highly are entirely dependent on the NAD salvage pathway for survival. We identify the previously unknown enhancer that underlies this dependence. Amplification of NAPRT is shown to generate a pharmacologically actionable tumour cell dependence for survival. Dependence on another rate-limiting enzyme of the NAD synthesis pathway, NAMPT, as a result of enhancer remodelling is subject to resistance by NMRK1-dependent synthesis of NAD. These results identify a central role for tissue context in determining the choice of NAD biosynthetic pathway, explain the failure of NAMPT inhibitors, and pave the way for more effective treatments.

Date: 2019
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DOI: 10.1038/s41586-019-1150-2

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