FASN plays a critical role in a number of

FASN plays a critical role in a number of metabolic functions by catalyzing the terminal steps in the synthesis of long-chain saturated fatty acids. There is a strong FASN expression and high enzymatic activity in many cancers especially in carcinomas (), while FASN is expressed at low levels in most normal tissues, except the liver, adipose tissue, and lactating mammary gland (), suggesting that cancer hcv protease inhibitor are more dependent on palmitate synthesis catalyzed by FASN than normal cells (). Palmitate and palmitate-derived lipids are essential components in cancer cell proliferation and survival as they provide energy metabolism and storage, membrane biosynthesis, and architecture and protein localization and activity. The well-documented upregulation of FASN in many human cancers as well as its association with poor clinical outcome () both strengthen the hypothesis that FASN is involved in the development, maintenance, and enhancement of the malignant phenotype. Interestingly, increased FASN expression has also been observed in some pre-neoplastic lesions and increases with tumor progression, supporting the hypothesis that the early up-regulation of FASN in precursor lesions might represent an obligatory metabolic acquisition that provides growth and survival advantages through multiple mechanisms. In the report by Ventura et al., the evidence for a role of FASN as a therapeutic target comes from both and models of human cancers. The authors found that pharmacological inhibition of FASN using TVB-3166 causes an increase in apoptosis in breast and prostate cancer cell lines. Interestingly, this response is not observed in non-cancer cells. These findings are consistent with previous reports that also used other FASN inhibitors (). The authors describe here unreported mechanisms of action including alteration on lipid raft architecture, palmitoylated protein localization disruption and inhibition of signal transduction through the PI3K-AKT-mTOR and ß-catenin pathways. The effect of TVB-3166 on lipid raft architecture was examined using immuno-fluorescent confocal microscopy to check palmitoylated protein localization. The data reveal that FASN inhibition disrupts lipid raft distribution in the membranes, altering the localization of raft-associated proteins such as N-Ras, inhibits multiple signal transduction pathways including PI3K-AKT-mTPOR and B-catenin, and modulating the expression of several genes in metabolic, proliferation and apoptosis pathways. In addition to experiments, Ventura et al. also present important results using models. The authors show that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. These results are globally in agreement with previous publication in which treatments with siRNA or chemical inhibitors of FASN have been shown to decrease tumor size in animal models of various types of cancers (). Finally, the authors performed both genetic and expression analyses and found that FASN inhibition modulates genes involved in lipid synthesis, signal transduction, cell cycle and apoptosis pathways. It may be very relevant for future development that those pathways were not affected in non-cancer cells. In conclusion, the results from this report show the potency, selectivity, reversible mechanism of action and availability of the FASN inhibitor TVB-3166, differentiating it from earlier FASN inhibitors such as C75 or cerulenin. The authors found that TVB-3166 modulates lipid synthesis, signal transduction, cell cycle and apoptosis pathways in both cell culture and tumor xenograft models. These results represent an important step in discovering the multiple mechanisms of action of FASN and pave the way for the identification of biomarkers with potential utility as predictive factors. Conflict of Interest Statement
For more than three decades patients diagnosed with stage III colorectal cancers have undergone adjuvant chemotherapy based on fluoropyrimidines (5-FU) and more recently in combination with oxaliplatin (). Overall that treatment has reduced the risk of tumor recurrence and improved survival for patients with resected colon cancer, but at present no validated biomarkers are available to predict the benefit of adjuvant chemotherapy in that group of patients. Up to now most efforts in CRC have been made to predict response to anti-EGFR therapy which is recommended now only to wild type KRAS and NRAS patients, but will most likely be followed by BRAF and PIK3CA in the near future (). For conventional 5-FU chemotherapy no companion biomarkers are available to predict therapy response, either for adjuvant or for curative protocols. Molecular heterogeneity of colon cancers is the main factor affecting the differential response to adjuvant chemotherapy. There are a lot of scientific articles reporting on biomolecules which can predict the response of that therapeutic approach. Among them MSI status (microsatellite instability) has already been shown to influence survival and response to adjuvant infusional 5-FU in colon cancer patients () since patients with MSI tumors have better outcomes as compared with patients with microsatellite stable (MSS) tumors. However, the improved prognosis is abrogated in the face of adjuvant 5-FU treatment (). In addition, thymidylate synthetase, EGFR polymorphisms and many others have been shown to influence progression free survival and therefore response to adjuvant treatment to 5-FU, but frequently with controversial results. In spite of the extensive scientific production no consensus on the use of a particular biomarker for therapy benefit prediction has been obtained. One of the reasons is that in several studies the impact of adjuvant 5-FU chemotherapy referred to specific biomarkers was not addressed to specific subgroups (stage II versus stage III patients). The discrimination between stages II and III is relevant because these two stages differ both at the clinical–biological level and at the molecular level. Moreover, prognostic markers for stage III have been reported to have no significance for stage II cancers ().