New Strategy For Inhibiting Ras Oncogene

Fighting cancer with a new approach to inhibiting the Ras oncogene pathway has a chance to succeed where others have failed. Aberrant Ras signaling turns on many cancers, so researchers have been trying to inhibit the Ras pathway for decades. But no inhibitor of Ras oncoprotein, Ras’s gene product, has survived clinical trials. The protein PDEδ helps shepherd Ras oncoprotein to cell membranes, where its signaling becomes activated. Now, Alfred Wittinghofer, Philippe I. H. Bastiaens, and Herbert Waldmann of the Max Planck Institute of Molecular Physiology, in Dortmund, Germany, and coworkers have identified an inhibitor, deltarasin, that blocks PDEδ-Ras interactions in vitro and reduces tumor growth in mice (Nature 2013, DOI: 10.1038/nature12205). They used screening methods to find compounds that block PDEδ-Ras interactions, combined two of the compounds, and optimized the combination to create deltarasin. The University of Utah’s Wolfgang Baehr, whose group has studied PDEδ, says deltarasin’s ability to inhibit tumor growth in mice “is clearly a success,” but side effects have yet to be evaluated. The Max Planck group is working with Lead Discovery Center, also in Dortmund, to test and improve deltarasin.