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.
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|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|
|Kaplan, Anna; Gaschler, Michael M; Dunn, Denise E et al. (2015) Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective. Proc Natl Acad Sci U S A 112:E2245-52|
|Woo, Jung Hoon; Shimoni, Yishai; Yang, Wan Seok et al. (2015) Elucidating Compound Mechanism of Action by Network Perturbation Analysis. Cell 162:441-51|
|Dixon, Scott J; Winter, Georg E; Musavi, Leila S et al. (2015) Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chem Biol 10:1604-9|
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