Most RAS drug targeting strategies focus on KRAS4B, due to the high KRAS mutation frequency in cancer and its high expression level. In addition, evidence suggests that KRAS4B (hereafter KRAS) but not HRAS is a potent driver of stemness traits in cancer cells. Exactly how KRAS promotes stemness and how this activity can be drug targeted is not understood.
PDE6D is a trafficking chaperone of farnesylated proteins, including KRAS. In addition to the plasma membrane, it facilitates trafficking to the primary cilium on the apical surface in particular of epithelial- and stem-cells. During asymmetric divisions of stem cells, the primary cilium associated mother centrosome is typically segregated to the stemness retaining cell. This allows for the earlier formation of the cilium from the more mature centriole acquired via the mother centrosome and thus sensitization for stemness signalling pathways localized in the cilium. KRAS could therefore traffic to the cilium to mediate stemness activity. Therfore, targeting PDE6D may be particularly relevant in order to inhibit a stemness-driving property of KRAS.
We will present our recent progress in understanding the role of PDE6D in trafficking KRAS to the cilium and novel sub-/low-nanomolar PDE6D inhibitors with the potential to block the KRAS driven stemness activity. Our mechanistic data suggest that combinations of PDE6D inhibitors with certain approved drugs should synergise and focus inhibition on the stemness driving ability of KRAS.