An easy, rapid and objective mathematical method to identify fatty acid synthase (oncogenic antigen-519) modulators with potential anticancer value

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.

Fatty Acid Synthase: A Target for the Reversal of Liver Steatosis

“…The question of which FAS inhibitor is best suited for which application is not necessarily clear-cut. In cancer, sensitivity to C75 for example was directly proportional to the level of FAS expression, and loss of sensitivity may be corrected with additional agents, which counteract FAS down-regulation [81].…”