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Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
An easy, rapid and objective mathematical method to identify fatty acid synthase (oncogenic antigen-519) modulators
Ruth Lupu1, Ramón Colomer, Javier A Menéndez
1Department of Medicine, Northwestern University Feinberg School of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA. r-lupu@northwestern.edu
Abstract:
Fatty acid synthase (FASN) is a novel druggable target for metabolically treating and preventing human malignancies. We envisioned that if loss of sensitivity to C75 (a slow-binding FASN inhibitor) occurs in parallel with loss of FASN expression and/or activity, a mathematical assessment of the nature of the interaction between investigational FASN modulators and C75 may predict the ability of experimental compounds to regulate FASN. We statistically compared the arithmetical sums of the anti-proliferative effects obtained when FASN modulators and C75 were used as single agents to those observed experimentally when agents were actually combined in a sequential schedule (i.e., FASN modulator-->C75). A reduced sensitivity to C75 (antagonism) occurred when compounds down-regulated FASN activity/expression, while an enhanced C75 efficacy (synergism) was found following exposure to FASN up-regulators. This "C75-sensitivity test" might offer an easy, rapid and objective method to identify FASN inhibitors with potential anticancer value in human cancer.
Insights
Fatty acid synthase (FASN) inhibitors show potential in cancer treatment. A new "C75-sensitivity test" predicts anticancer efficacy by assessing how compounds affect FASN activity and C75 response.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Fatty acid synthase (FASN) is a key enzyme in cancer metabolism and a promising drug target.
- Developing effective FASN inhibitors is crucial for cancer therapy.
- Understanding drug interactions is vital for predicting treatment outcomes.
Purpose of the Study:
- To develop a predictive method for identifying effective FASN inhibitors.
- To assess the interaction between novel FASN modulators and the FASN inhibitor C75.
- To establish a 'C75-sensitivity test' for evaluating anticancer potential.
Main Methods:
- Statistically comparing the anti-proliferative effects of single agents versus combined sequential treatment (FASN modulator followed by C75).
- Analyzing the impact of investigational FASN modulators on FASN expression and activity.
- Quantifying changes in C75 sensitivity (synergism or antagonism) in response to FASN modulators.
Main Results:
- Compounds that down-regulated FASN activity/expression led to reduced C75 sensitivity (antagonism).
- Compounds that up-regulated FASN activity/expression resulted in enhanced C75 efficacy (synergism).
- The observed effects correlated with mathematical predictions of drug interactions.
Conclusions:
- The 'C75-sensitivity test' provides a rapid and objective method for identifying potential anticancer FASN inhibitors.
- This assay can predict whether novel compounds will enhance or diminish the efficacy of C75.
- This approach aids in the selection of promising FASN-targeting agents for human cancer treatment.
