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

Constitutively active Pas proteins, their regulatory components, and overexpressed tyrosine kinase receptors that activate Pas, are frequently associated with cell transformation in human tumors. This suggests that functional Pas antagonists may have anti-tumor activity. Studies in rodent fibroblasts have shown that S-trans, transfarnesylthiosalicylic acid (FTS) acts as a rather specific nontoxic Pas antagonist, dislodging Pas from its membrane anchorage domains and accelerating its degradation. FTS is not a farnesyltransferase 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 inhibited tumor growth in Panc-1 xenografted nude mice, apparently without systemic toxicity. Daily FTS treatment (5 mg/kg intraperitoneallly) in mice with tumors (mean volume 0.07 cm(3)) markedly decreased tumor growth (after treatment for 18 days, tumor volume had increased by only 23+/-30-fold in the FTS-treated group and by 127+/-66-fold in controls). These findings suggest that FTS represents a new class of functional Pas antagonists with potential therapeutic value.