A new functional Ras antagonist inhibits human pancreatic tumor growth in nude mice

Constitutively active Pas proteins, their regulatory components, and overex pressed tyrosine kinase receptors that activate Pas, are frequently associa ted with cell transformation in human tumors. This suggests that functional Pas antagonists may have anti-tumor activity. Studies in rodent fibroblast s have shown that S-trans, transfarnesylthiosalicylic acid (FTS) acts as a rather specific nontoxic Pas antagonist, dislodging Pas from its membrane a nchorage domains and accelerating its degradation. FTS is not a farnesyltra nsferase inhibitor, and does not affect Pas maturation. Here we demonstrate that FTS also acts as a functional Pas antagonist in human pancreatic cell lines that express activated K-Ras (Panc-1 and MiaPaCa-2). In Panc-1 cells , FTS at a concentration of 25-100 mu M reduced the amount of Pas in a dose -dependent manner and interfered with serum-dependent and epidermal growth factor-stimulated ERK activation, thus inhibiting both anchorage-dependent and anchorage-independent growth of Panc-1 cells in vitro. FTS also inhibit ed tumor growth in Panc-1 xenografted nude mice, apparently without systemi c toxicity. Daily FTS treatment (5 mg/kg intraperitoneallly) in mice with t umors (mean volume 0.07 cm(3)) markedly decreased tumor growth (after treat ment for 18 days, tumor volume had increased by only 23+/-30-fold in the FT S-treated group and by 127+/-66-fold in controls). These findings suggest t hat FTS represents a new class of functional Pas antagonists with potential therapeutic value.