title: Cancer stem cell drugs target K-ras signaling in a stemness context.
abstract: Cancer stem cells (CSCs) are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. Salinomycin is the most established CSC inhibitor. However, its primary mechanistic target is still unclear, impeding the discovery of compounds with similar anti-CSC activity. Here, we show that salinomycin very specifically interferes with the activity of K-ras4B, but not H-ras, by disrupting its nanoscale membrane organization. We found that caveolae negatively regulate the sensitivity to this drug. On the basis of this novel mechanistic insight, we defined a K-ras-associated and stem cell-derived gene expression signature that predicts the drug response of cancer cells to salinomycin. Consistent with therapy resistance of CSC, 8% of tumor samples in the TCGA-database displayed our signature and were associated with a significantly higher mortality. Using our K-ras-specific screening platform, we identified several new candidate CSC drugs. Two of these, ophiobolin A and conglobatin A, possessed a similar or higher potency than salinomycin. Finally, we established that the most potent compound, ophiobolin A, exerts its K-ras4B-specific activity through inactivation of calmodulin. Our data suggest that specific interference with the K-ras4B/calmodulin interaction selectively inhibits CSC.
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
authors.forename: A K
authors.initials: AK
authors.lastname: Najumudeen
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Jaiswal
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
authors.forename: B
authors.initials: B
authors.lastname: Lectez
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
authors.forename: C
authors.initials: C
authors.lastname: Oetken-Lindholm
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
authors.forename: C
authors.initials: C
authors.lastname: Guzmán
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Siljamäki
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
authors.forename: I M D
authors.initials: IM
authors.lastname: Posada
authors.affiliation: Microbial Screening Technologies Pty. Ltd., Building C, Smithfield, New South Wales, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Lacey
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: T
authors.initials: T
authors.lastname: Aittokallio
authors.affiliation: Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
authors.forename: D
authors.initials: D
authors.lastname: Abankwa
mesh_terms: D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000235:genetics; D021941:Caveolae / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010080:Oxazoles / Q000008:administration & dosage; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics*; D011714:Pyrans / Q000008:administration & dosage; D054830:Sesterterpenes / Q000008:administration & dosage*; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D000095662:Polyether Polyketides
chemical_list: D002147:Calmodulin; D010080:Oxazoles; D016283:Proto-Oncogene Proteins p21(ras); D011714:Pyrans; D054830:Sesterterpenes; D018631:ras Proteins; C117307:KRAS protein, human; C040764:ophiobolin A; C010327:salinomycin; D000095662:Polyether Polyketides; C022800:conglobatin