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Statins are widely prescribed inhibitors of the mevalonate pathway, acting to lower systemic cholesterol levels. The mevalonate pathway is critical for tumorigenesis and is frequently upregulated in cancer. Nonetheless, reported effects of statins on tumor progression are ambiguous, making it unclear whether statins, alone or in combination, can be used for chemotherapy. Here, using advanced mass spectrometry and isotope tracing, we showed that statins only modestly affected cancer cholesterol homeostasis. Instead, they significantly reduced synthesis and levels of another downstream product, the mitochondrial electron carrier coenzyme Q, both in cultured cancer cells and tumors. This compromised oxidative phosphorylation, causing severe oxidative stress. To compensate, cancer cells upregulated antioxidant metabolic pathways, including reductive carboxylation, proline synthesis, and cystine import. Targeting cystine import with an xCT transporter–lowering MEK inhibitor, in combination with statins, caused profound tumor cell death. Thus, statin-induced ROS production in cancer cells can be exploited in a combinatorial regimen. Significance: Cancer cells induce specific metabolic pathways to alleviate the increased oxidative stress caused by statin treatment, and targeting one of these pathways synergizes with statins to produce a robust antitumor response. See related commentary by Cordes and Metallo, p. 151

The “Warburg effect” describes a peculiar metabolic feature of many solid tumors, namely their increased glucose uptake and high glycolytic rates, which allow cancer cells to accumulate building blocks for the biosynthesis of macromolecules. During aerobic glycolysis, pyruvate is preferentially metabolized to lactate by the enzyme lactate dehydrogenase-A (LDH-A), suggesting a possible vulnerability at this target for small-molecule inhibition in cancer cells. In this study, we used FX11, a small-molecule inhibitor of LDH-A, to investigate this possible vulnerability in a panel of 15 patient-derived mouse xenograft (PDX) models of pancreatic cancer. Unexpectedly, the p53 status of the PDX tumor determined the response to FX11. Tumors harboring wild-type (WT) TP53 were resistant to FX11. In contrast, tumors harboring mutant TP53 exhibited increased apoptosis, reduced proliferation indices, and attenuated tumor growth when exposed to FX11. [18F]-FDG PET-CT scans revealed a relative increase in glucose uptake in mutant TP53 versus WT TP53 tumors, with FX11 administration downregulating metabolic activity only in mutant TP53 tumors. Through a noninvasive quantitative assessment of lactate production, as determined by 13C magnetic resonance spectroscopy (MRS) of hyperpolarized pyruvate, we confirmed that FX11 administration inhibited pyruvate-to-lactate conversion only in mutant TP53 tumors, a feature associated with reduced expression of the TP53 target gene TIGAR, which is known to regulate glycolysis. Taken together, our findings highlight p53 status in pancreatic cancer as a biomarker to predict sensitivity to LDH-A inhibition, with regard to both real-time noninvasive imaging by 13C MRS as well as therapeutic response. Cancer Res; 75(16); 3355–64. ©2015 AACR.

Background and Aim: Tumor cells depend on metabolic alterations for their continued growth and survival, and such changes make cancer cells peculiarly addicted to the rapacious uptake of glucose. The Warburg effect is such a metabolic feature of cancers that helps to preferentially metabolize pyruvate via glycolytic pathway to lactate by lactate dehydrogenase A (LDHA). Our recent findings indicated that LDHA is required not only for tumor initiation but for tumor maintenance and progression (Le et al., PNAS, 2010). Here, we investigated the therapeutic potential of LDHA inhibition in pancreatic cancer, and attempt to delineate the factors responsible for tumor response. Methods: We evaluated the in vivo efficacy of FX11, a small molecule inhibitor of LDHA, in a panel of pancreatic cancer xenografts with annotated mutational status. Non-invasive quantitative assessment of lactate production was measured by real-time hyperpolarization experiments with 1-13C-labeled pyruvate using a DNP polarizer (HyperSense). [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET) combined with computed tomography (CT) imaging was conducted to evaluate the effect of FX11 treatment on glucose metabolism. Liquid chromatography - mass spectrometry (LC-MS) was used to quantify the tumor metabolites. Ki-67 and TUNEL staining were performed to determine the effect of FX11 treatment on apoptosis and tumor cell proliferation. Results: p53-deficient pancreatic cancer xenografts showed higher baseline metabolic activity and FX11 treatment down-regulated the tumor metabolic activity. Real-time imaging of pyruvate to lactate conversion using nuclear magnetic resonance (NMR) spectroscopy revealed that FX11 treatment inhibits pyruvate to lactate conversion in p53-deficient pancreatic cancer xenografts. Importantly, p53 promotes the expression of TP53-induced glycolysis regulator (TIGAR) and loss of p53 in tumors results in reduced TIGAR levels. The metabolic profiles of p53-deficient versus p53-proficient pancreatic cancer xenografts were remarkably different. FX11 treatment attenuates tumor progression, induces apoptosis and reduces tumor cell proliferation, preferentially in p53-deficient pancreatic cancer xenografts. Conclusions: Because the Warburg effect is characteristic of virtually all cancers and p53 is frequently mutated in vast majority of human cancers, our finding that p53, a key regulator of glycolysis and a major factor deciding the therapeutic outcome of targeting the Warburg effect may have broad clinical implications. Our findings may help to identify patient subsets that may be particularly responsive to LDHA targeted agents in clinical trials. Acknowledgement: Stand Up To Cancer-AACR Dream Team Translational Cancer Research Grant No. SU2C-AACR DT0509. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-61. doi:1538-7445.AM2012-LB-61