Resistance of a variant ras-transformed cell line to phenotypic reversion by farnesyl transferase inhibitors.

Abstract

Pharmacological inhibitors of the housekeeping enzyme farnesyl transferase (FT) inhibit the growth of ras-transformed cells in vitro and in vivo without antiproliferative effects on normal cells. In one direction to analyze the basis for this selectivity and to study modes of drug resistance that arise in animals, we characterized a variant ras-transformed cell line, 749r-1, which was resistant to phenotypic reversion with FT inhibitors. The transformed phenotype, growth potential, and actin cytoskeleton of 749r-1 cells were unaffected by treatment with the FT inhibitor 1-739,749 at concentrations up to 30-fold higher than those sufficient to revert ras-transformed cells. Resistance correlated 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 endogenous FT to drug inhibition. These effects were not due to mutation of the FT subunits, changes in intracellular drug accumulation, or amplification of the multiple drug resistance gene (MDR). However, a similar reduction in the ability of L-739,749 to inhibit Ras farnesylation was also seen in ras-transformed cells rendered resistant by ectopic expression of farnesyl-independent RhoB, suggesting some mechanistic overlap. We concluded that 749r-1 cells sustained a stable alteration that conferred drug resistance by a novel mechanism.