Fig. 7.

Model describing the mechanism of increased anti-tumor efficacy with combined FASN inhibition and taxane treatment compared to single-agent treatment. Right panel: cellular palmitate synthesized by FASN is utilized for many cellular functions that include (1) post-translational modification of proteins including alpha- and beta-tubulin, (2) synthesis of complex lipids required for cellular metabolism and energy storage, and (3) maintenance of plasma membrane architecture to support oncogenic signaling (Ventura et al., 2015). Left panel: inhibition of FASN causes a loss of tubulin palmitoylation, depletes lipid stores that maintain tumor cell metabolism, and disrupts the plasma membrane architecture necessary for oncogenic signaling. Diminished tubulin palmitoylation and expression and altered microtubule organization sensitize tumor cells to taxane activity. Taxane activity limits the capacity of a tumor cell to adapt to FASN inhibition and causes sustained disruption of biological processes that utilize palmitate, perhaps interfering with the ability of tumor cells to acquire palmitate exogenously or utilize palmitate that is not synthesized de novo by the tumor cell.