RESISTANCE OF A VARIANT RAS-TRANSFORMED CELL-LINE TO PHENOTYPIC REVERSION BY FARNESYL TRANSFERASE INHIBITORS

Pharmacological inhibitors of the housekeeping enzyme farnesyl transfe rase (FT) inhibit the growth of ms-transformed cells in vitro and in v ivo without antiproliferative effects on normal cells, In one directio n to analyze the basis for this selectivity and to study modes of drug resistance that arise in animals, we characterized a variant ras-tran sformed cell line, 749(r)-1, which was resistant to phenotypic reversi on with FT inhibitors, The transformed phenotype, growth potential, an d actin cytoskeleton of 749(r)-1 cells were unaffected by treatment wi th the FT inhibitor L-739,749 at concentrations up to 30-fold higher t han those sufficient to revert ras-transformed cells, Resistance corre lated with a reduced ability of L-739,749 to inhibit the farnesylation of Ras and lamin B and with a reduction in the susceptibility of endo genous FT to drug inhibition, These effects were not due to mutation o f the FT subunits, changes in intracellular drug accumulation, or ampl ification of the multiple drug resistance gene (MDR). However, a simil ar reduction in the ability of L-739,749 to inhibit Ras farnesylation was also seen in ras-transformed cells rendered resistant by ectopic e xpression of farnesyl-independent RhoB, suggesting some mechanistic ov erlap, We concluded that 749(r)-1 cells sustained a stable alteration that conferred drug resistance by a novel mechanism.