Tumors have high energetic and anabolic needs for rapid cell growth and proliferation1, and the serine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes2,3. We integrated metabolic tracing and transcriptional profiling of a large panel of non–small cell lung cancer (NSCLC) cell lines to characterize the activity and regulation of the serine/glycine biosynthetic pathway in NSCLC. Here we show that the activity of this pathway is highly heterogeneous and is regulated by NRF2, a transcription factor frequently deregulated in NSCLC. We found that NRF2 controls the expression of the key serine/glycine biosynthesis enzyme genes PHGDH, PSAT1 and SHMT2 via ATF4 to support glutathione and nucleotide production. Moreover, we show that expression of these genes confers poor prognosis in human NSCLC. Thus, a substantial fraction of human NSCLCs activates an NRF2-dependent transcriptional program that regulates serine and glycine metabolism and is linked to clinical aggressiveness.
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We thank G. Poulogiannis for bioinformatics advice and H. Abbasi, C. Klimko and M. Yuan for technical support with mass spectrometry experiments. This work was supported by US National Institutes of Health grants P01 CA117969 and R01 GM041890 (L.C.C.), R01 CA157996-01 (R.J.D.), 5R01 CA152301 (Y.X.) and P50 CA70907 (J.D.M., I.I.W., Y.X. and K.E.H.) and by Cancer Prevention Research Institute of Texas (CPRIT) funding to J.D.M., Y.X., I.I.W. and K.E.H. (RP110708 and RP120732) and R.J.D. (RP130272). P.-H.C. was supported by a grant from the Welch Foundation to R.J.D. (I-1733). The mass spectrometry work was partially supported by US National Institutes of Health grants 5P30 CA006516 and 5 P01 CA120964 (J.M.A.). G.M.D. was the Malcolm A.S. Moore Hope Funds for Cancer Research Fellow and is supported by the PanCAN/AACR Pathway to Leadership grant.
L.C.C. owns equity in, receives compensation from and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals. Agios Pharmaceuticals is identifying metabolic pathways in cancer cells and developing drugs to inhibit such enzymes to disrupt tumor cell growth and survival. R.J.D. is on the scientific advisory boards of Agios Pharmaceuticals and Peloton Therapeutics. Peloton Therapeutics is developing drugs to target altered molecular pathways in cancer, including altered metabolism.
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DeNicola, G., Chen, PH., Mullarky, E. et al. NRF2 regulates serine biosynthesis in non–small cell lung cancer. Nat Genet 47, 1475–1481 (2015). https://doi.org/10.1038/ng.3421
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