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

AK Najumudeen, A Jaiswal, Benoit Lectez, Christina Oetken, Camilo A Guzman Gutierrez, E Siljamaki, Posada IMD, E Lacey, T Aittokallio, Daniel Abankwa

Research output: Contribution to journalArticleScientificpeer-review

48 Citations (Scopus)

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.
Original languageUndefined/Unknown
Pages (from-to)5248–5262
Number of pages15
JournalOncogene
Volume35
Issue number40
DOIs
Publication statusPublished - 2016
MoE publication typeA1 Journal article-refereed

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