Compounds that selectively eliminate tumor cells with an aberrant genotype may provide a greater therapeutic index and allow for genotype-based patient selection. After screening >1 million compounds for those with oncogenic-RAS-selective-lethality, we have identified four oncogenic-Ras-selective lethal scaffolds (RSL scaffolds) that we named erastin, RSL3, ML162 and SRS7-31. We have elucidated key aspects of their mechanism of action, including: (1) these compounds are more potent in tumor cells with constitutive activation of the RAS-RAF- MEK pathway, (2) they cause a form of iron-dependent oxidative cell death that is morphologically, genetically and biochemically distinct from apoptosis, necrosis, autophagic cell death and necroptosis, which we have termed ferroptosis, and (3) they ultimately cause tumor- selective lipid peroxidation, resulting in membrane damage and non-apoptotic cell death. Here, we seek to test and extend our hypothesis that tumors harboring activated RAS-RAF- MEK signaling are sensitized to ferroptosis. This hypothesis will be evaluated in vitro and in vivo, as these compounds are validated, to move testing of this mechanism and these compounds towards a clinical setting. The significance of the proposed research is that it will result in validation of a set of lead compounds and associated mechanisms that allow for selective targeting of tumor cells harboring oncogenic mutations in Ras pathway genes, especially pancreatic cancers, almost all of which have activating KRAS mutations.
Our goal is to test and extend our hypothesis that tumor cells harboring activating mutations in RAS genes are sensitized to a newly discovered form of non-apoptotic cell death. Furthermore, we aim to create optimized compounds that could eventually serve as therapeutic agents for patients with tumors containing these genetic alterations.
| Welsch, Matthew E; Kaplan, Anna; Chambers, Jennifer M et al. (2017) Multivalent Small-Molecule Pan-RAS Inhibitors. Cell 168:878-889.e29 |
| Gaschler, Michael M; Stockwell, Brent R (2017) Lipid peroxidation in cell death. Biochem Biophys Res Commun 482:419-425 |
| Viswanathan, Vasanthi S; Ryan, Matthew J; Dhruv, Harshil D et al. (2017) Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547:453-457 |
| Distéfano, Ayelén Mariana; Martin, María Victoria; Córdoba, Juan Pablo et al. (2017) Heat stress induces ferroptosis-like cell death in plants. J Cell Biol 216:463-476 |
| Yang, Wan Seok; Kim, Katherine J; Gaschler, Michael M et al. (2016) Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci U S A 113:E4966-75 |
| Hayano, M; Yang, W S; Corn, C K et al. (2016) Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23:270-8 |
| Shimada, Kenichi; Skouta, Rachid; Kaplan, Anna et al. (2016) Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol 12:497-503 |
| Shimada, Kenichi; Hayano, Miki; Pagano, Nen C et al. (2016) Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as Biomarker for Ferroptosis Sensitivity. Cell Chem Biol 23:225-235 |
| Yang, Wan Seok; Stockwell, Brent R (2016) Ferroptosis: Death by Lipid Peroxidation. Trends Cell Biol 26:165-176 |
| Larraufie, Marie-Helene; Yang, Wan Seok; Jiang, Elise et al. (2015) Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility. Bioorg Med Chem Lett 25:4787-92 |
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