Cancer stem cell drugs target K-ras signaling in a stemness context

• Published in: Oncogene Vol. 35; no. 40; pp. 5248 - 5262
• Main Authors: Najumudeen, A K, Jaiswal, A, Lectez, B, Oetken-Lindholm, C, Guzmán, C, Siljamäki, E, Posada, I M D, Lacey, E, Aittokallio, T, Abankwa, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.10.2016; Nature Publishing Group
• Subjects: 13/31; 14/19; 14/33; 38/39; 38/43; 631/154/1435/2417; 631/67/71; 631/80/86; Apoptosis; Calcium binding proteins; Calmodulin - antagonists & inhibitors; Calmodulin - genetics; Cancer; Caveolae - drug effects; Cell Biology; Drugs; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Human Genetics; Humans; Internal Medicine; MCF-7 Cells; Medical research; Medicine; Medicine & Public Health; Membranes; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Oncology; Original; original-article; Oxazoles - administration & dosage; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - genetics; Pyrans - administration & dosage; ras Proteins - antagonists & inhibitors; ras Proteins - genetics; Sesterterpenes - administration & dosage; Stem cells
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.59

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.