Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as Biomarker for Ferroptosis Sensitivity

• Published in: Cell chemical biology Vol. 23; no. 2; pp. 225 - 235
• Main Authors: Shimada, Kenichi, Hayano, Miki, Pagano, Nen C., Stockwell, Brent R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 18.02.2016
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biomarkers, Tumor - analysis; Biomarkers, Tumor - metabolism; cancer pharmacology; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; drug mechanisms of action; Drug Screening Assays, Antitumor; ferroptosis; Humans; NADP - analysis; NADP - metabolism; NADPH; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Pharmacogenetics; pharmacogenomics; Precision Medicine; tumor biomarkers; NADPH; cancer pharmacology; pharmacogenomics; ferroptosis; tumor biomarkers; drug mechanisms of action
• ISSN: 2451-9456; 2451-9448; 2451-9456; 2451-9448
• DOI: 10.1016/j.chembiol.2015.11.016

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. [Display omitted] •Cell-line-selective lethal compounds are consistent across pharmacogenomic studies•Compounds with distinct sensitivity profiles indicate distinct mechanisms of action•The GI50 profiles of ferroptosis inducers are cell-line selective and unique•Basal NADP(H) level correlates with sensitivity to ferroptosis inducers Large-scale compound profiling across cancer cell lines has been of interest, but discrepancies between different projects have been suggested. The methodology of Shimada et al. allows for consistent analyses of such data and identifies robust biomarkers for drug sensitivity, including NADPH as a biomarker for ferroptosis-inducing compounds.