1. Pan-Cancer Metabolic Signature Predicts Co-Dependency on Glutaminase and De Novo Glutathione Synthesis Linked to a High-Mesenchymal Cell State
- Author
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Marie Evangelista, Michelle Nannini, Wendy Sandoval, Kyung Song, Deepak Sampath, Ron Firestein, Thomas Hunsaker, Sheerin Latham, Min Gao, Mandy Kwong, Anneleen Daemen, Dewakar Sangaraju, Bianca M. Liederer, Allan Jaochico, Bonnie Liu, Rebecca Hong, Xiaofeng Zhao, Georgia Hatzivassiliou, David A. Peterson, and Cecile de la Cruz
- Subjects
0301 basic medicine ,Drug ,Lung Neoplasms ,Bioenergetics ,Physiology ,media_common.quotation_subject ,Glutamate-Cysteine Ligase ,Mice, Nude ,Breast Neoplasms ,Glutathione synthesis ,Mice, SCID ,Biology ,Citric Acid ,03 medical and health sciences ,Mice ,Breast cancer ,Glutaminase ,Cell Line, Tumor ,Databases, Genetic ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Lung cancer ,Molecular Biology ,Tumor Stem Cell Assay ,media_common ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,medicine.disease ,Glutathione ,Xenograft Model Antitumor Assays ,Isoenzymes ,030104 developmental biology ,Enzyme ,HEK293 Cells ,chemistry ,Cancer research ,Metabolome ,Female - Abstract
Summary The enzyme glutaminase (GLS1) is currently in clinical trials for oncology, yet there are no clear diagnostic criteria to identify responders. The evaluation of 25 basal breast lines expressing GLS1, predominantly through its splice isoform GAC, demonstrated that only GLS1-dependent basal B lines required it for maintaining de novo glutathione synthesis in addition to mitochondrial bioenergetics. Drug sensitivity profiling of 407 tumor lines with GLS1 and gamma-glutamylcysteine synthetase (GCS) inhibitors revealed a high degree of co-dependency on both enzymes across indications, suggesting that redox balance is a key function of GLS1 in tumors. To leverage these findings, we derived a pan-cancer metabolic signature predictive of GLS1/GCS co-dependency and validated it in vivo using four lung patient-derived xenograft models, revealing the additional requirement for expression of GAC above a threshold (log2RPKM + 1 ≥ 4.5, where RPKM is reads per kilobase per million mapped reads). Analysis of the pan-TCGA dataset with our signature identified multiple indications, including mesenchymal tumors, as putative responders to GLS1 inhibitors.
- Published
- 2016