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Mutations in Ras GTPase and various other components of the Ras signaling pathways are among the most common genetic alterations in human cancers and have also been identified in several familial/developmental syndromes. Ras is also an important factor in many cancers where it is not mutated but functionally activated through inappropriate function of other signal transduction elements. One such example is the overexpression of growth factor receptors in glioblastoma (GBM). Elucidating the mechanistic details of the GTPase reaction has been an important scientific goal and the subject of intensive research for many years. However to this day, targeting Ras directly remains elusive. Our laboratory recently demonstrated that Src binds to and phosphorylates Ras on a conserved tyrosine residue markedly reducing the binding of effector Raf to Ras and concomitantly increasing the rate of GTP hydrolysis leading to Ras inactivation. Furthermore we demonstrate that tyrosine phosphorylated Ras can be dephosphorylated by the phosphatase SHP2 resulting in Ras activation. We also demonstrate that increased Ras activity in human primary GBM cell lines and astrocytes derived from GBM-prone mice, as well as in human GBM patient samples results from elevated SHP2 activity. Finally we show that the highly specific SHP2 inhibitor II-B08 promotes tyrosine phosphorylation of Ras leading to attenuation of downstream proliferative MAPK/ERK signaling and reduction in tumor burden in mouse models of GBM.

CS-02 * SHP2 PROMOTES TUMOR PROGRESSION IN GBM VIA RAS ACTIVATION