PDEδ interference impedes the proliferation and survival of oncogenic KRas expressing human cancer cell lines

Abstract

Ras proteins, most notably isoform KRas4B are frequently mutated oncogenes in numerous human cancers and associated with poor prognosis. Despite ambitious research affords since the discovery of Ras proteins as human oncogenes in 1982, no pharmacological therapy approach reached the clinic yet and Ras is still viewed as “undruggable” protein. For signal propagation, Ras proteins have to be localized at the plasma membrane. Enrichment there is facilitated by spatial cycles that utilize the prenyl binding protein PDEδ as solubilizing factor. Thus, instead of targeting Ras proteins directly, interference with its spatial organization by targeting PDEδ was studied as promising alternative. First generations of small molecule inhibitors of PDEδ were reported to selectively affect proliferation of oncogenic KRas-dependent human pancreatic ductal adenocarcinoma cell lines.

Here, we characterize the activity of a new small molecule inhibitor chemotype called Deltasonamide in cells. We show that Deltasonamide administration leads to a depletion of KRas from the plasma membrane and report enhanced anti-proliferative effects of the high affinity inhibitor in oncogenic KRas-dependent human pancreatic ductal adenocarcinoma cell lines, for the first time at sub-micromolar concentrations.

Furthermore, we demonstrate that PDEδ inhibition is also an applicable tool to interfere with aberrant KRas signaling in human colorectal cancer cell lines. Both PDEδ knock down and small molecule inhibition selectively reduced proliferation and viability of colorectal cancer cell lines harboring oncogenic KRas mutations, whereas cell lines expressing only wild type KRas were not affected by interference with PDEδ. Moreover, we report an interdependence of oncogenic KRas activity and PDEδ’s solubilizing function that is manifested in the correlation of both proteins within the cell lines and well reflected in the distinct survivability after PDEδ interference.

Together, our results show that PDEδ is a valid therapeutic target in both pancreatic ductal adenocarcinoma and colorectal cancer harboring oncogenic KRas mutations.