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Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression.

Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M, Buckley D, Kemble G, Heuer TS - EBioMedicine (2015)

Bottom Line: Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays.Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific.Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses.

View Article: PubMed Central - PubMed

Affiliation: 3-V Biosciences, Menlo Park, CA, United States.

ABSTRACT

Unlabelled: Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage-independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics.

Research in context: Fatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers.

No MeSH data available.


Related in: MedlinePlus

FASN inhibition blocks metabolic and signal transduction pathways vital to cancer cell growth, proliferation, and survival. FASN inhibition results in inhibition of Akt and S6 phosphorylation in the AKT–mTOR signal transduction pathway. In the Wnt–β-catenin pathway, FASN inhibition results in the inhibition of Lrp6 and β-catenin phosphorylation as well as the expression of TCF promoter-driven genes such as c-Myc. FASN inhibition impairs the plasma membrane localization of palmitoylated and other lipid-raft-associated proteins such as N-Ras. Our data fit a model whereby the disruption of lipid rafts and mislocalization of membrane-associated proteins can drive inhibition of signaling through cellular growth and survival pathways such as AKT–mTOR and Wnt–β-catenin. Signal transduction through molecules such as K-Ras or pathways such as AKT–mTOR is tightly linked with tumor cell metabolism of glucose and glutamine as well as lipid biosynthesis.
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f0045: FASN inhibition blocks metabolic and signal transduction pathways vital to cancer cell growth, proliferation, and survival. FASN inhibition results in inhibition of Akt and S6 phosphorylation in the AKT–mTOR signal transduction pathway. In the Wnt–β-catenin pathway, FASN inhibition results in the inhibition of Lrp6 and β-catenin phosphorylation as well as the expression of TCF promoter-driven genes such as c-Myc. FASN inhibition impairs the plasma membrane localization of palmitoylated and other lipid-raft-associated proteins such as N-Ras. Our data fit a model whereby the disruption of lipid rafts and mislocalization of membrane-associated proteins can drive inhibition of signaling through cellular growth and survival pathways such as AKT–mTOR and Wnt–β-catenin. Signal transduction through molecules such as K-Ras or pathways such as AKT–mTOR is tightly linked with tumor cell metabolism of glucose and glutamine as well as lipid biosynthesis.

Mentions: TVB-3166 inhibits tumor growth in patient-derived non-small cell lung xenograft tumors with both mutant and wild type KRAS mutation status, as well as with adenocarcinoma and squamous cell carcinoma histology. Both in vitro and in vivo data suggest that FASN inhibition may be effective in K-Ras-mutant non-small-cell lung tumors. KRAS mutations are prevalent in other tumor types such as colorectal and pancreatic adenocarcinomas. Our data shows that TVB-3166 also inhibits growth of the KRAS-mutant PANC-1 xenograft tumor. Mutations in KRAS have been linked to altered metabolic features of tumor cells, including pancreatic adenocarcinomas where KRAS mutations are found in more than 95% of all tumors (Donahue et al., 2012, Jones et al., 2008, Yachida et al., 2010, Ying et al., 2012). Mutant K-Ras has been shown to reprogram tumor cell metabolism and cause increased dependency on glutamine and glucose metabolism (Son et al., 2013). A consequence of this altered metabolic state is the increased production of pyruvate. Pyruvate can be metabolized to lactate to generate ATP and acetyl-CoA or, alternatively, can be shunted to citrate and then acetyl-CoA, which is a substrate for palmitate biosynthesis by FASN (Fig. 8). Thus, mutant K-Ras may increase the dependency of tumor cells on de novo lipogenesis and provide a biological basis for targeting these tumors, or a subset of them, with a FASN inhibitor.


Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression.

Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M, Buckley D, Kemble G, Heuer TS - EBioMedicine (2015)

FASN inhibition blocks metabolic and signal transduction pathways vital to cancer cell growth, proliferation, and survival. FASN inhibition results in inhibition of Akt and S6 phosphorylation in the AKT–mTOR signal transduction pathway. In the Wnt–β-catenin pathway, FASN inhibition results in the inhibition of Lrp6 and β-catenin phosphorylation as well as the expression of TCF promoter-driven genes such as c-Myc. FASN inhibition impairs the plasma membrane localization of palmitoylated and other lipid-raft-associated proteins such as N-Ras. Our data fit a model whereby the disruption of lipid rafts and mislocalization of membrane-associated proteins can drive inhibition of signaling through cellular growth and survival pathways such as AKT–mTOR and Wnt–β-catenin. Signal transduction through molecules such as K-Ras or pathways such as AKT–mTOR is tightly linked with tumor cell metabolism of glucose and glutamine as well as lipid biosynthesis.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4563160&req=5

f0045: FASN inhibition blocks metabolic and signal transduction pathways vital to cancer cell growth, proliferation, and survival. FASN inhibition results in inhibition of Akt and S6 phosphorylation in the AKT–mTOR signal transduction pathway. In the Wnt–β-catenin pathway, FASN inhibition results in the inhibition of Lrp6 and β-catenin phosphorylation as well as the expression of TCF promoter-driven genes such as c-Myc. FASN inhibition impairs the plasma membrane localization of palmitoylated and other lipid-raft-associated proteins such as N-Ras. Our data fit a model whereby the disruption of lipid rafts and mislocalization of membrane-associated proteins can drive inhibition of signaling through cellular growth and survival pathways such as AKT–mTOR and Wnt–β-catenin. Signal transduction through molecules such as K-Ras or pathways such as AKT–mTOR is tightly linked with tumor cell metabolism of glucose and glutamine as well as lipid biosynthesis.
Mentions: TVB-3166 inhibits tumor growth in patient-derived non-small cell lung xenograft tumors with both mutant and wild type KRAS mutation status, as well as with adenocarcinoma and squamous cell carcinoma histology. Both in vitro and in vivo data suggest that FASN inhibition may be effective in K-Ras-mutant non-small-cell lung tumors. KRAS mutations are prevalent in other tumor types such as colorectal and pancreatic adenocarcinomas. Our data shows that TVB-3166 also inhibits growth of the KRAS-mutant PANC-1 xenograft tumor. Mutations in KRAS have been linked to altered metabolic features of tumor cells, including pancreatic adenocarcinomas where KRAS mutations are found in more than 95% of all tumors (Donahue et al., 2012, Jones et al., 2008, Yachida et al., 2010, Ying et al., 2012). Mutant K-Ras has been shown to reprogram tumor cell metabolism and cause increased dependency on glutamine and glucose metabolism (Son et al., 2013). A consequence of this altered metabolic state is the increased production of pyruvate. Pyruvate can be metabolized to lactate to generate ATP and acetyl-CoA or, alternatively, can be shunted to citrate and then acetyl-CoA, which is a substrate for palmitate biosynthesis by FASN (Fig. 8). Thus, mutant K-Ras may increase the dependency of tumor cells on de novo lipogenesis and provide a biological basis for targeting these tumors, or a subset of them, with a FASN inhibitor.

Bottom Line: Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays.Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific.Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses.

View Article: PubMed Central - PubMed

Affiliation: 3-V Biosciences, Menlo Park, CA, United States.

ABSTRACT

Unlabelled: Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage-independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20-200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K-AKT-mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics.

Research in context: Fatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers.

No MeSH data available.


Related in: MedlinePlus