# Adaptation to cystine limitation stress confers a targetable lipid metabolism vulnerability in pancreatic ductal adenocarcinoma

## TL;DR

Pancreatic cancer cells adapt to low cystine levels by reprogramming their metabolism, which can be targeted with lomitapide to stop tumor growth.

## Contribution

The study reveals a new metabolic vulnerability in pancreatic cancer cells under cystine limitation stress and proposes lomitapide as a potential treatment.

## Key findings

- Adaptation to cystine limitation stress promotes tumor growth via upregulation of the oxidative pentose phosphate pathway.
- Lomitapide inhibits triacylglyceride synthesis and lipid reprogramming, reducing tumor growth and sensitizing to chemotherapy.
- Cystine limitation stress leads to lipidomic reprogramming involving triacylglycerides and lipid droplet formation.

## Abstract

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. On the other hand, CLSA-mediated lipidomic reprogramming depends on triacylglycerides synthesis and lipid droplet formation to mitigate lipotoxicity. Through drug screening, we identify lomitapide as an inhibitor of CLSA PDAC tumor growth and a potent sensitizer of chemotherapy. Lomitapide inhibits triacylglycerides synthesis to interfere with CLSA and chemotherapy-induced lipidomic reprogramming. Taken together, we demonstrate that CLSA promotes PDAC tumor growth through metabolic reprogramming and lomitapide could be used to target the dysregulated lipid metabolism in PDAC.

Cystine levels in pancreatic ductal adenocarcinoma (PDAC) tumour microenvironment are deficient, despite its crucial role for cancer cell maintenance. Here, the authors show that adaptation to cystine limitation stress promotes PDAC growth through induces metabolic reprogramming to promote PDAC tumor growth, while conferring a vulnerability in lipid metabolism targetable by lomitapide.