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Background  Pancreatic ductal adenocarcinomas (PDA) activate a glutamine-dependent pathway of cytosolic nicotinamide adenine dinucleotide phosphate (NADPH) production to maintain redox homeostasis and support proliferation. Enzymes involved in this pathway ( GLS1  (mitochondrial glutaminase 1),  GOT1  (cytoplasmic glutamate oxaloacetate transaminase 1), and  GOT2  (mitochondrial glutamate oxaloacetate transaminase 2)) are highly upregulated in PDA, and among these, inhibitors of  GLS1  were recently deployed in clinical trials to target anabolic glutamine metabolism. However, single-agent inhibition of this pathway is cytostatic and unlikely to provide durable benefit in controlling advanced disease.    Results  Here, we report that reducing NADPH pools by genetically or pharmacologically (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) or CB-839) inhibiting glutamine metabolism in mutant Kirsten rat sarcoma viral oncogene homolog ( KRAS ) PDA sensitizes cell lines and tumors to ß-lapachone (ß-lap, clinical form ARQ761). ß-Lap is an NADPH:quinone oxidoreductase ( NQO1 )-bioactivatable drug that leads to NADPH depletion through high levels of reactive oxygen species (ROS) from the futile redox cycling of the drug and subsequently nicotinamide adenine dinucleotide (NAD)+ depletion through poly(ADP ribose) polymerase ( PARP ) hyperactivation.  NQO1  expression is highly activated by mutant  KRAS  signaling. As such, ß-lap treatment concurrent with inhibition of glutamine metabolism in mutant  KRAS ,  NQO1  overexpressing PDA leads to massive redox imbalance, extensive DNA damage, rapid  PARP -mediated NAD+ consumption, and PDA cell death—features not observed in  NQO1 -low, wild-type  KRAS  expressing cells.    Conclusions  This treatment strategy illustrates proof of principle that simultaneously decreasing glutamine metabolism-dependent tumor anti-oxidant defenses and inducing supra-physiological ROS formation are tumoricidal and that this rationally designed combination strategy lowers the required doses of both agents  in vitro  and  in vivo . The non-overlapping specificities of  GLS1  inhibitors and ß-lap for PDA tumors afford high tumor selectivity, while sparing normal tissue.    Electronic supplementary material  The online version of this article (doi:10.1186/s40170-015-0137-1) contains supplementary material, which is available to authorized users.

Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone