FAT1 Enhances the Sensitivity of Non-Small Cell Lung Cancer to VCP Inhibitors by Regulating the Activation of the Endoplasmic Reticulum Stress Pathway

ABSTRACT

FAT atypical cadherin 1 (FAT1) is prevalently expressed in non-small cell lung cancer (NSCLC) tissues and is associated with poor prognosis in patients. Using data from the PRISM Repurposing drug sensitivity database, we observed that among compounds related to protein homeostasis, the valosin-containing protein (VCP) inhibitor CB-5083 demonstrated the most significant variation in sensitivity among NSCLC cells, categorized according to FAT1 expression levels. Notably, CB-5083 markedly inhibits cell proliferation and induces apoptosis in NSCLC cells with high expression of FAT1. Targeting VCP may trigger strong endoplasmic reticulum stress (ER stress) in NSCLC cells, leading to inhibition of cell proliferation in tumor cells. Mechanically, knockdown of FAT1 stimulates YAP signaling and target gene transcription, thereby attenuating the UPR pathway signal induced by CB-5083 stimulation in NSCLC cells. Our results suggest that FAT1 regulates the activation of the ER stress pathway through YAP signaling, influencing the susceptibility of NSCLC cells to VCP inhibitors. These insights provide novel perspectives for NSCLC treatment and extend the therapeutic applications of VCP inhibitors in clinical settings.

Graphical Abstract

This study reveals that FAT1 modulates the activation of the endoplasmic reticulum stress pathway through YAP signaling, thereby influencing the sensitivity of NSCLC cells to VCP inhibitors. These findings suggest that NSCLC with high FAT1 expression may demonstrate increased susceptibility to VCP-targeted inhibitors and other endoplasmic reticulum stress-inducing therapies. This not only provides a novel perspective for clinical pharmacological treatment of NSCLC but also offers insights for further development and application of VCP inhibitors currently in clinical research.