Isotype-specific Ras center dot GTP-levels predict the efficacy of farnesyl transferase inhibitors against human astrocytomas regardless of Ras mutational status

Previous studies have demonstrated that astrocytomas express elevated level s of activated Ras(.)GTP despite the absence of activating Ras mutations. F arnesyl transferase inhibitors (FTIs) exert their antitumor effect in part through inhibition of Pas-mediated signaling. SCH66336 is a potent FTI pres ently undergoing clinical trials in patients with solid tumors. We evaluate d the efficacy of SCH66336 against a panel of eight human astrocytoma cell lines and three human astrocytoma explant xenograft models in NOD-SCID mice . SCH66336 demonstrated variable antiproliferative effects against the cell lines, with IC50 ranging from 0.6 muM to 32.3 muM. Two of the three human glioblastoma multiforme (GBM) xenografts demonstrated substantial growth in hibition in response to SCH66336, with up to 69% growth inhibition after 21 days of treatment. Drug efficacy could be accurately predicted using a com bination of the H-, K-, and N-isotype-specific Ras GTP levels. These data i ndicate that the absence of Ras mutations does not preclude chemotherapeuti c efficacy by FTIs, that Ras is likely a major target of FTIs regardless of Ras mutational status, and that isotype-specific Ras GTP levels are a prom ising marker of drug efficacy.