Diacylglycerol Metabolism and Signaling Is a Driving Force Underlying FASN Inhibitor Sensitivity in Cancer Cells

Fatty
acid synthase (FASN) generates the de novo source
of lipids for cell proliferation and is a promising cancer
therapy target. Development of FASN inhibitors, however, necessitates
a better understanding of sensitive and resistant cancer types to
optimize patient treatment. Indeed, testing the cytotoxic effects
of FASN inhibition across human cancer cells revealed diverse sensitivities.
We show here that metabolic incorporation of glucose into specific
complex lipid species strongly predicts FASN inhibitor sensitivity.
We also show that the levels of one of these lipid classes, protein
kinase C (PKC) stimulator diacylglycerols, are lowered upon FASN inhibitor
treatment in sensitive compared to resistant cells and that PKC activators
and inhibitors rescue cell death in sensitive cells and sensitize
resistant cells, respectively. Our findings not only reveal a biomarker
for predicting FASN sensitivity in cancer cells but also a put forth
a heretofore unrecognized mechanism underlying the anticancer effects
of FASN inhibitors.