title: Mitochondrial electron transport is the cellular target of the oncology drug elesclomol.
abstract: Elesclomol is a first-in-class investigational drug currently undergoing clinical evaluation as a novel cancer therapeutic. The potent antitumor activity of the compound results from the elevation of reactive oxygen species (ROS) and oxidative stress to levels incompatible with cellular survival. However, the molecular target(s) and mechanism by which elesclomol generates ROS and subsequent cell death were previously undefined. The cellular cytotoxicity of elesclomol in the yeast S. cerevisiae appears to occur by a mechanism similar, if not identical, to that in cancer cells. Accordingly, here we used a powerful and validated technology only available in yeast that provides critical insights into the mechanism of action, targets and processes that are disrupted by drug treatment. Using this approach we show that elesclomol does not work through a specific cellular protein target. Instead, it targets a biologically coherent set of processes occurring in the mitochondrion. Specifically, the results indicate that elesclomol, driven by its redox chemistry, interacts with the electron transport chain (ETC) to generate high levels of ROS within the organelle and consequently cell death. Additional experiments in melanoma cells involving drug treatments or cells lacking ETC function confirm that the drug works similarly in human cancer cells. This deeper understanding of elesclomol's mode of action has important implications for the therapeutic application of the drug, including providing a rationale for biomarker-based stratification of patients likely to respond in the clinical setting.
authors.affiliation: Synta Pharmaceuticals Corp., Lexington, Massachusetts, United States of America.
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Blackman
authors.forename: Kahlin
authors.initials: K
authors.lastname: Cheung-Ong
authors.forename: Marinella
authors.initials: M
authors.lastname: Gebbia
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.forename: Suqin
authors.initials: S
authors.lastname: He
authors.forename: Jane
authors.initials: J
authors.lastname: Kepros
authors.forename: Aurelie
authors.initials: A
authors.lastname: Jonneaux
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
authors.forename: Jerome
authors.initials: J
authors.lastname: Kluza
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Rao
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Wada
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003300:Copper / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D006834:Hydrazines; D017382:Reactive Oxygen Species; C512195:elesclomol; D003300:Copper