@article{5e69a3c810b14a23b08f6d9b19b2aafe,
title = "Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma",
abstract = "Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma.",
keywords = "GATOR, PHGDH, SAMTOR, lipid metabolism, mTORC1, methotrexate, one-carbon metabolism, osteosarcoma, perhexiline, serine biosynthesis",
author = "Richa Rathore and Caldwell, {Katharine E.} and Charles Schutt and Brashears, {Caitlyn B.} and Prudner, {Bethany C.} and Ehrhardt, {William R.} and Leung, {Cheuk Hong} and Heather Lin and Daw, {Najat C.} and Beird, {Hannah C.} and Abigail Giles and Wang, {Wei Lien} and Lazar, {Alexander J.} and Chrisinger, {John S.A.} and Livingston, {J. Andrew} and {Van Tine}, {Brian A.}",
note = "Funding Information: The authors thank Abigail Godec, Angela Hirbe, Jason Held, Jieya Shao, Kian Lim, Nhi Le, and Breelyn Wilky for helpful discussion and advice. This project was supported by an anonymous donor, Dawn Merkel's Bad to the Bone Chili Cook Off, Kellsie's Hope Foundation, and the Sarcoma Foundation of America. This project was also supported by funding from NIH grant R01CA227115 and the Washington University surgical oncology training grant T32CA009621. The authors thank Laura Shelton for guidance with analysis of metabolomics data from Human Metabolome Technologies, NanoString for guidance with analysis, the Washington University Diabetes Research Center (NIH grant 5 P30 DK020579) for use of the Seahorse Bioanalyzer, and the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Immunomonitoring Laboratory, which provided the Luminex FlexMap service. The Siteman Cancer Center is supported in part by an NCI cancer center support grant P30 CA091842. R.R. K.E.C. C.S. C.B.B. B.C.P. W.R.E. W.-L.W. C.H.L. H.L. N.C.D. H.C.B. A.G. A.J.L. J.S.A.C. J.A.L. and B.A.V.T. contributed to the research and/or data analysis; R.R. and B.A.V.T. conceptualized and directed the study; and R.R. C.S. B.C.P. and B.A.V.T. designed and/or interpreted the experiments (with input from the other co-authors) and wrote the manuscript. All authors discussed the results and provided comments on the manuscript. B.C.P. declares current employment at Aveda. B.A.V.T. declares grants from Merck; grants and personal fees from Pfizer; grants from TRACON Pharmaceuticals; grants, personal fees, and other remunerations from GlaxoSmithKline; personal fees from Polaris Inc.; personal fees from Lilly; personal fees from Caris Life Sciences; personal fees from Novartis; personal fees from CytRX; personal fees from Plexxikon; personal fees from Epizyme; personal fees from Daiichi Sankyo; personal fees from Adaptimmune; personal fees from Immune Design; personal fees from Bayer; personal fees from Cytokinetics; and personal fees from Deciphera; he has a patent issued for the use of ME1 as a biomarker and ACXT3102. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2021",
month = jan,
day = "26",
doi = "10.1016/j.celrep.2020.108678",
language = "English",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
number = "4",
}