Fatty acid synthase in chemoresistance: mechanisms and therapeutic opportunities

Chemoresistance has been a major obstacle to the efficient treatment of cancer. Recently, targeting lipid metabolism has gained significant attention because of its roles not only in promoting cancer progression but also in inducing chemotherapy resistance. Fatty acid synthase (FAS) is the sole enzyme that is in charge of catalyzing the synthesis of palmitate, a long-chain lipid that is essential for membrane construction and post-translational modification in cell biology. Both FAS and its product, palmitate, have been validated as critical players in mediating or causing chemoresistance in cancers, although the details remain elusive, requiring further basic studies. In this mini-review, we provide a brief and concise overview of the basic research on FAS in cancer and its mechanisms of inducing chemoresistance. More importantly, we summarize and critically discuss the progress of small-molecule FAS inhibitors, especially those in clinical trials. While by far, several FAS inhibitors, including denifanstat and omeprazole, have demonstrated beneficial effects in clinical trials, no candidate has been approved by the FDA. We concluded here that targeting FAS is a feasible strategy to overcome chemoresistance, although more interdisciplinary efforts are needed to identify a potent, specific, and bioavailable FAS inhibitor for clinical applications.