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.