Farnesyl protein transferase inhibitors (FTIs) have demonstrated clinical 
activity in certain solid tumors and hematological malignancies. Little is known 
about mechanisms of resistance to these agents. To provide a basis for better 
understanding FTI resistance, the colorectal carcinoma cell line HCT 116 was 
selected by stepwise exposure to increasing 
4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide 
(SCH66336) concentrations. The resulting line, HCT 116R, was 100-fold resistant 
to SCH66336 and other FTIs, including methyl 
{N-[2-phenyl-4-N[2(R)-amino-3-mercaptopropylamino] benzoyl]}-methionate 
(FTI-277), but was less than 2-fold resistant to the standard agents 
gemcitabine, cisplatin, and paclitaxel. Accumulation of the unfarnesylated forms 
of prelamin A and HDJ-2, two substrates that reflect farnesyl transferase 
inhibition, was similar in FTI-treated parental and HCT 116R cells, indicating 
that alterations in drug uptake or inhibition of farnesyl protein transferase is 
not the mechanism of resistance. Changes in signal-transduction pathways that 
might account for this resistance were examined by immunoblotting and confirmed 
pharmacologically. There was no difference in activation of the 
mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated 
kinase pathway or sensitivity to the MEK1/2 inhibitor 2'-amino-3'-methoxyflavone 
(PD98059) in HCT 116R cells. In contrast, increased phosphorylation of the 
molecular target of rapamycin (mTOR) and its downstream target p70 S6 kinase and 
increased levels of Akt1 and Akt2 were demonstrated in HCT 116R cells. Further 
experiments demonstrated that the mTOR inhibitor rapamycin selectively 
sensitized HCT 116R cells to SCH66336 but not to gemcitabine, cisplatin, or 
paclitaxel. These findings provide evidence that alterations in the 
phosphatidylinositol-3 kinase/Akt pathway can contribute to FTI resistance and 
suggest a potential strategy for overcoming this resistance.