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

## TL;DR

Blocking a key lipid-making pathway makes prostate cancer cells more vulnerable to a common chemotherapy drug by increasing drug entry into the cells.

## Contribution

Demonstrates that inhibiting SREBP-dependent lipogenesis enhances chemotherapy efficacy in prostate cancer.

## Key findings

- Inhibiting SREBP with FGH10019 increases docetaxel-induced cell death in prostate cancer cells.
- Reduced lipid biosynthesis shifts lipid composition to polyunsaturated lipids, increasing membrane permeability.
- Increased membrane permeability leads to higher intracellular docetaxel accumulation.

## Abstract

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.