Targeting SREBP-dependent lipogenesis potentiates the anti-tumor activity of docetaxel by increasing membrane permeability and intracellular drug accumulation

Lipid metabolism is among the most frequently dysregulated metabolic processes in human cancer, yet how cellular lipids, the end products of lipogenesis, and their composition are altered to support various aspects of cancer remains poorly understood. Here, we show that targeting SREBP-dependent lipogenesis via FGH10019, an orally available SREBP inhibitor, enhances docetaxel-induced cytotoxicity in human prostate cancer cells in vitro and in vivo. Mechanistically, suppression of lipid biosynthesis leads to a shift in cellular lipid composition toward polyunsaturated lipids, resulting in increased membrane permeability and intracellular docetaxel accumulation. Thus, our findings reveal a critical role of de novo lipogenesis in protecting cancer cells from chemotherapeutics and suggest that treatment with lipogenesis inhibitors could improve the efficacy of chemotherapy against human prostate cancer.