Abstract
Targeting the KRAS–PDEδ interaction inhibits KRAS-dependent signaling and tumor growth.
Major finding: Targeting the KRAS–PDEδ interaction inhibits KRAS-dependent signaling and tumor growth.
Concept: Solubilization of farnesylated KRAS by PDEδ sustains KRAS membrane localization and signaling.
Impact: Small molecules that interfere with RAS trafficking may offer a way to directly inhibit RAS signaling.
RAS proteins undergo several posttranslational modifications required for association with the plasma membrane and normal and oncogenic signaling, but efforts to indirectly inhibit RAS signaling by inhibiting the enzymes responsible for these modifications have had disappointing results. Previous studies have shown that the delta subunit of cGMP phosphodiesterase (PDEδ) binds and promotes the cytoplasmic diffusion of farnesylated RAS proteins and is required for their distribution to the plasma membrane. Hypothesizing that directly targeting the interaction between PDEδ and RAS could disrupt RAS plasma membrane localization and block RAS signaling, Zimmermann and colleagues performed a high-throughput screen for small molecules that bound the farnesyl-binding pocket of His-tagged PDEδ and disrupted binding to a biotinylated and farnesylated KRAS peptide. A structure-guided design approach based on the structure of a hit compound in complex with PDEδ led to the identification of a soluble, cell-permeable derivative that was named deltarasin. Fluorescence lifetime imaging microscopy-based fluorescence resonance energy transfer measurements showed that deltarasin disrupted the interaction between fluorescently labeled KRAS and PDEδ in live cells and induced insolubilization and redistribution of KRAS away from the plasma membrane to intracellular membranes. Deltarasin also strongly reduced the proliferation and survival of KRAS-mutant human pancreatic ductal adenocarcinoma (PDAC) cell lines in association with decreased downstream ERK phosphorylation but had relatively little effect on proliferation or ERK activation in KRAS–wild-type PDAC cells. Furthermore, intraperitoneal injection of deltarasin almost completely blocked the growth of KRAS-mutant PDAC xenografts and significantly reduced tumor volume relative to vehicle-injected control animals. Although further studies are needed to characterize potential off-target effects of inhibiting PDEδ binding to farnesylated proteins, these findings provide a framework for the development of compounds that directly inhibit RAS activity by interfering with its spatial organization.
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