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.

SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling

“…It was recently suggested that K-ras is the major driver of stem cell or progenitor cell proliferation, while H-ras drives differentiation (75)(76)(77). Therefore, SPRED1's well-documented role in regulating differentiation (2) may integrate in the following way, according to our differential Ras regulation scenario outlined above.…”

Calmodulin and PI3K Signaling in KRAS Cancers

“…Nonetheless, the ambitious and arduous road toward obtaining beneficial drugs that work in the clinic to abolish CaM’s action still lies ahead. We note that recently, ophiobolin A was established to work by targeting K-Ras signaling in a stemness context by blocking CaM [88], which can be viewed as a step toward this aim.…”

From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

“…In contrast, KLF4 expression was suppressed in KRAS mutant colon cancer cells, which is consistent with its induction of multiple cell lineage differentiation in the intestine 18 . Additionally, a KRAS-centric mechanism would apply in the context of epidermal-mesenchymal transition (EMT) to generate CSCs through the WNT pathway 170 . …”

“…Le Rolle et al 18 showed that inhibition of KRAS mutant colon tumors with miR145, an epigenetic regulator and an embryonic stem cell inhibitor, suppressed their malignant growth. Data suggest that salinomycin, the most potent cancer stem cell inhibitor with potential efficacy in human cancers, specifically disrupts KRAS onc nanoscale membrane organization, effectively reducing effector recruitment to KRAS onc , which then compromised at least MAPK signaling and proliferation 170 . Ophiobolin A, another candidate CSC drug, has been found to possess higher potency than salinomycin and exert its KRAS4B-specific activity through the inactivation of calmodulin 170 .…”