@article{f7f44118d77b4e2584678e4495a1b4fe,
title = "De novo serine biosynthesis from glucose predicts sex-specific response to antifolates in non-small cell lung cancer cell lines",
abstract = "Lung cancer is the leading cause of cancer-related death. Intriguingly, males with non-small cell lung cancer (NSCLC) have a higher mortality rate than females. Here, we investigated the role of serine metabolism as a predictive marker for sensitivity to the antifolate pemetrexed in male and female NSCLC cell lines. Using [13C6] glucose tracing in NSCLC cell lines, we found that a subset of male cells generated significantly more serine from glucose than female cells. Higher serine biosynthesis was further correlated with increased sensitivity to pemetrexed in male cells only. Concordant sex differences in metabolic gene expression were evident in NSCLC and pan-cancer transcriptome datasets, suggesting a potential mechanism with wide-reaching applicability. These data were further validated by integrating antifolate drug cytotoxicity and metabolic pathway transcriptome data from pan-cancer cell lines. Together, these findings highlight the importance of considering sex differences in cancer metabolism to improve treatment for all patients.",
keywords = "Cancer, Cell biology, Cellular physiology",
author = "Jasmin Sponagel and Siddhartha Devarakonda and Rubin, {Joshua B.} and Jingqin Luo and Ippolito, {Joseph E.}",
note = "Funding Information: This work was supported by the Cancer Biology Pathway Molecular Oncology Training Grant NIH T32CA113275 (J.S.), the NIH grants K99/R00 CA218869 (JEI), R21 CA242221 (J.E.I.), R01 CA174737-06 (J.B.R.), the Alvin J. Siteman Cancer Center Investment Program/The Foundation for Barnes-Jewish Hospital (J.B.R. J.E.I.) and the Barnard Research Fund (J.B.R. J.E.I.), and Joshua's Great Things (J.B.R.). The authors gratefully acknowledge the Transdisciplinary Research in Energetics and Cancer (TREC) Training Workshop R25CA203650 (PI: Melinda Irwin). The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. This paper is dedicated to the memory of Karen Ippolito. Conceptualization: J.S. S.D. and J.E.I. Investigation and formal analysis: J.S. J.L. and J.E.I. performed and analyzed experiments; J.S. J.L. and J.E.I. helped with data collection and analysis; Data curation: J.L. Supervision: S.D. and J.E.I. Visualization: J.S. J.L. and J.E.I. Writing – original and revised draft: J.S. and J.E.I. Writing – review & editing: All authors. Funding acquisition: J.B.R. and J.E.I. S.D. serves on the advisory board of Genentech. We worked to ensure diversity in experimental samples through the selection of the cell lines. We worked to ensure diversity in experimental samples through the selection of the genomic datasets. Funding Information: This work was supported by the Cancer Biology Pathway Molecular Oncology Training Grant NIH T32CA113275 (J.S.), the NIH grants K99/R00 CA218869 (JEI), R21 CA242221 (J.E.I.), R01 CA174737-06 (J.B.R.), the Alvin J. Siteman Cancer Center Investment Program/The Foundation for Barnes-Jewish Hospital (J.B.R., J.E.I.) and the Barnard Research Fund (J.B.R., J.E.I.), and Joshua{\textquoteright}s Great Things (J.B.R.). The authors gratefully acknowledge the Transdisciplinary Research in Energetics and Cancer (TREC) Training Workshop R25CA203650 (PI: Melinda Irwin). The results shown here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga . This paper is dedicated to the memory of Karen Ippolito. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = nov,
day = "18",
doi = "10.1016/j.isci.2022.105339",
language = "English",
volume = "25",
journal = "iScience",
issn = "2589-0042",
number = "11",
}