# Vaccinia-related kinase 2 inhibition elicits vulnerability of glutathione metabolism in pancreatic cancer

## TL;DR

This study shows that inhibiting VRK2 makes pancreatic cancer cells more vulnerable to targeting glutathione metabolism, offering a new approach for precision cancer therapy.

## Contribution

The study reveals a novel link between VRK2 inhibition and glutathione metabolism vulnerability in pancreatic cancer.

## Key findings

- VRK2-deficient pancreatic cancer cells are more susceptible to glutathione pathway inhibition.
- VRK2 inhibition reduces SLC7A11 plasma membrane expression, impairing GSH biosynthesis.
- VRK2-deficient cells are more prone to ferroptosis due to low glutathione levels.

## Abstract

Metabolic reprogramming has garnered significant attention in recent years due to its therapeutic potential in cancer treatment. However, identifying responsive tumor subpopulations remains a major obstacle in developing metabolism-targeted therapies, as metabolic vulnerabilities vary among cancers with different oncogene expression profiles. Therefore, elucidating the association between oncogene expression and metabolic characteristics could enable more precise metabolic interventions in clinical settings. Using pharmacological approaches, we demonstrate that VRK2-deficient pancreatic cancer (PC) cells exhibit heightened vulnerability to glutathione (GSH) metabolic pathway inhibition. This susceptibility stems from reduced basal GSH levels caused by impaired plasma membrane expression of SLC7A11. Mechanistically, we reveal that VRK2 inhibition disrupts endoplasmic reticulum (ER)-to-Golgi trafficking of SLC7A11, consequently diminishing GSH biosynthesis and predisposing PC cells to ferroptosis. Collectively, our findings establish a novel link between the oncogene VRK2 and GSH synthesis metabolism, providing a molecular basis for developing stratified metabolic therapies for PC patients.