title: Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as Biomarker for Ferroptosis Sensitivity.
abstract: Precision medicine in oncology requires not only identification of cancer-associated mutations but also effective drugs for each cancer genotype, which is still a largely unsolved problem. One approach for the latter challenge has been large-scale testing of small molecules in genetically characterized cell lines. We hypothesized that compounds with high cell-line-selective lethality exhibited consistent results across such pharmacogenomic studies. We analyzed the compound sensitivity data of 6,259 lethal compounds from the NCI-60 project. A total of 2,565 cell-line-selective lethal compounds were identified and grouped into 18 clusters based on their median growth inhibitory GI50 profiles across the 60 cell lines, which were shown to represent distinct mechanisms of action. Further transcriptome analysis revealed a biomarker, NADPH abundance, for predicting sensitivity to ferroptosis-inducing compounds, which we experimentally validated. In summary, incorporating cell-line-selectivity filters improves the predictive power of pharmacogenomic analyses and enables discovery of biomarkers that predict the sensitivity of cells to specific cell death inducers.
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA. Electronic address: ks2474@columbia.edu.
authors: Kenichi
authors: K
authors: Shimada
authors: Department of Pharmacology, Columbia University, New York, NY 10027, USA.
authors: Miki
authors: M
authors: Hayano
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors: Nen C
authors: NC
authors: Pagano
authors: Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Department of Chemistry, Columbia University, New York, NY 10027, USA; Howard Hughes Medical Institute, Columbia University, 1208 Northwest Corner Building, MC 4846, 550 West 120th Street, New York, NY 10027, USA. Electronic address: bstockwell@columbia.edu.
authors: Brent R
authors: BR
authors: Stockwell
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009249:NADP / Q000032:analysis* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010597:Pharmacogenetics; D057285:Precision Medicine
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009249:NADP
keywords: NADPH; cancer pharmacology; drug mechanisms of action; ferroptosis; pharmacogenomics; tumor biomarkers