Although preclinical studies showed that FTIs induce tumor growth inhibition rather than tumor regression and their ultimate targets in cells remained largely unde fined, they entered clinical trials. Promisingly, FTIs synergize with taxanes and show some efficacy in the treatment of breast cancer when administrated in com binatorial therapy. Unfortunately, when administrated as a single agent, they failed clinical trials at stage III for most of the malignancies tested, with the notable excep tion of haematological malignancies. This failure has been largely attributed to the scarce knowledge of how FTIs ultimately act in the cell. Collectively, clinical and preclinical studies have shown that FTIs are anti proliferative agents that have low toxicity for normal cells.

Moreover, the efficacy of structurally diverse FTI molecules is highly consistent in different organisms, showing that they act via a con served mechanism in eukaryotic cells. Proteomic approaches aimed at identifying proteins differentially prenylated upon FTI treatment have shown that, in addition to Ras oncoproteins, DNAJ, laminin A, nucleo some assembly protein NAP 1, peroxisomal biogenesis factor 1 and annexin are differentially prenylated using FTIs at clinically relevant dosages. More classical biochemical approaches related FTI anti proliferative action to defects in the attachment of farnesylated pro teins, such as CENP E and CENP F, to kinetochores or poor prenylation of RheB. Unfortunately, the correct minimal balance of farnesylated and non far nesylated proteins within cells is often unknown.

Taken together, these approaches have been unable so far to clearly correlate the FTI antiproliferative action with the prenylation status of a given protein basically due to i the large number of farnesylated proteins in human cells. ii their multiple roles Anacetrapib in different processes lead ing to proliferation and, last but not least, iii the diffi culty in correlating the lack of prenylation of an FTase target with the FTI antiproliferative action. To predict FTI efficacy at the clinical level it is neces sary to devise novel genomic strategies to further deci pher how FTIs ultimately affect cellular activity. Which off targets they might affect and how FTI resistance is achieved are major challenges for todays studies.

Pro mising results towards the goal of predicting FTI effi cacy in clinical practice were recently reported by profiling the expression signatures of newly diagnosed Acute myelogenous leukemia patients treated with TIPIFARNIB. The ratio of expression levels of two genes, RASGRP and APTX, appears to be predictive of the Tipifarnib response in AML patients, although it remains unclear how this might operate. From the above it is clear that a better knowledge of FTI action at the cellular level is required.